Deuterated compounds and uses thereof

ABSTRACT

The present invention relates to deuterated and optionally detectably labeled compounds of formula (I) and formula (V): 
     
       
         
         
             
             
         
       
     
     and salts thereof, wherein R 1 , R 2 , A, and X 10 -X 19  have any of the values defined in the specification. Also included are pharmaceutical compositions comprising such compounds and salts, and methods of using such compounds and salts as imaging agents.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of International Application No.PCT/EP2015/060447, filed May 12, 2015, which claims the benefit ofpriority of U.S. Provisional Application No. 61/992,717, filed May 13,2014, the entirety of each of which is incorporated by reference in itsentirety.

BACKGROUND OF THE INVENTION

Neurofibrillary tangles (NFTs) deposits are a hallmark of a variety ofneuropathologies such as Alzheimer's disease (AD), progressivesupranuclear palsy, frontotemporal dementia and parkinsonism linked tochromosome 17, Pick's disease, and dementia pugilistica. NFT plaques arecomprised of aggregated hyperphosphorylated tau protein. Tau is aprotein associated with cytoskeleton and involved in the transport ofvesicles along microtubules in neurons. Under pathological conditions,tau is hyperphosphorylated and forms beta-sheet aggregates withfibrillar appearances similar to Aβ in senile plaques. Some tau-targetedtherapies aim to slow disease progression by interfering withcell-to-cell transfer of soluble tau oligomers capable infectingadjacent cells by a prion mechanism. Alternatively, tau-targetedtherapies aim to inhibit tau oligomerization and/or aggregation tolarger fibrils and tangles (Bulic, B., et al., J. Med. Chem., 2013 56(11), 4135-55). Such strategies warrant reliable non-invasivetau-specific biomarkers for monitoring of current tau burden and diseaseprogression. Tau-specific PET imaging biomarkers have the potential tonon-invasively monitor disease progression and also provide a directreadout of tau-targeted agent efficacy and confirmation of its mechanismof action in clinical trials (Mathis, C. A.; Klunk, W. E., Neuron 201379 (6), 1035-7; and Jensen, J. R., et al., J. Alzheimer's Disease:JAD2011 26 Suppl 3, 147-57).

Several tau-selective molecules were recently discovered andradiolabeled with positron emitting radionuclides for PET imaging. Oneof them, [¹⁸F][A] was reported to bind tau aggregates in AD patienttissues with 22 nM affinity and demonstrated 27-fold selectivity for tauover Aβ amyloid which forms similarly structured fibrils. Initialclinical evaluation of [A] demonstrated its ability to clearlydifferentiate between AD patients and age matched controls. Moreover,the PET tracer distribution in patients with increasing MMSE scoreresembled tau localization described by the Braak score (Braak, H., etal., Acta Neuropathol 2006 112 (4), 389-404) found postmortem in tissuesof patients with corresponding AD severity. Unfortunately, the oxidativemetabolism of [A] led to dissociation of ¹⁸F from the molecule andaccumulation of ¹⁸F fluoride in mineral bone. The undesired skull uptakecan potentially interfere with quantification of cortical uptake of thetracer. See Xia, C. F., et al., Alzheimer's Dement. 2013 9 (6), 666-76;Zhang, W., et al., J. Alzheimer's Disease:JAD 2012 31 (3), 601-12;Chien, D. T., et al., J. Alzheimer's Disease:JAD 2013 34 (2), 457-68;and Chien, D. T., et al., J. Alzheimer's Disease:JAD 2014 38 (1),171-84.

Currently there is a need for additional detectable compounds that bindto tau. In particular, there is a need for detectable compounds withimproved in vivo properties, such as improved metabolismcharacteristics.

SUMMARY OF THE INVENTION

In one aspect the invention includes a deuterated detectable compound,or salt thereof, that binds to a tau protein.

Another aspect includes a compound of formula (I) or formula (V):

or a salt thereof, wherein:

R¹ is phenyl, naphthyl, 6-membered heteroaryl, 9- or 10-memberedbicyclic heterocyclyl, 12-13 membered tricyclic carbocyclyl, or 12-13membered tricyclic heterocyclyl, wherein R¹ is optionally substitutedwith one or more groups R^(a), wherein R¹ is attached to the remainderof the compound of formula (I) at any synthetically feasible position;

A is absent, C₁₋₄alkylene, C₃₋₆cycloalkylene, C₂₋₄alkenylene, orC₂₋₄alkynylene;

R² is 6-, 9-, or 10-membered carbocyclyl or a 5-, 6-, 9-, or 10-memberedheterocyclyl, which carbocyclyl and heterocyclyl is optionallysubstituted with one or more groups R^(b), wherein R² is attached to theremainder of the compound of formula (I) at any synthetically feasibleposition;

each X₁₀-X₁₇ is independently CH or N;

X₁₈ is CH, N, O, or S; and

X₁₉ is CH, C, or N;

each ---- is independently absent or forms a double bond, provided onlyone ---- forms a double bond;

each R^(a) is independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(c), carbocyclyl, heterocyclyl, halo,—NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(v))₂, —S(O)—N(R^(v))₂,—S(O)₂—N(R^(v))₂, —O—R^(v), —S—R^(v), —O—C(O)—R^(v), —O—C(O)—O—R^(v),—C(O)—R^(v), —C(O)—O—R^(v), —S(O)—R^(v), —S(O)₂—R^(v),—O—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—OR^(v), —N(R^(v))—C(O)—N(R^(v))₂,—N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v), —N(R^(v))—S(O)₂—R^(v),—N(R^(v))—S(O)—N(R^(v))₂, and —N(R^(v))—S(O)₂—N(R^(v))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(c),carbocyclyl, and heterocyclyl is optionally substituted with one or moregroups independently selected from oxo, halo, —NO₂, —N(R^(v))₂, —CN,—C(O)—N(R^(v))₂, —S(O)—N(R^(v))₂, —S(O)₂—N(R^(v))₂, —O—R^(v), —S—R^(v),—O—C(O)—R^(v), —C(O)—R^(v), —C(O)—O—R^(v), —S(O)—R^(v), —S(O)₂—R^(v),—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v),—N(R^(v))—S(O)₂—R^(v), C₂-C₆ alkenyl, R^(ay), and C₁₋₆alkyl that isoptionally substituted with one or more groups independently selectedfrom oxo and halo;

each R^(b) is independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(d), carbocyclyl, heterocyclyl, halo,—NO₂, —N(R^(w))₂, —CN, —C(O)—N(R^(w))₂, —S(O)—N(R^(w))₂,—S(O)₂—N(R^(w))₂, —O—R^(w), —S—R^(w), —O—C(O)—R^(w), —O—C(O)—O—R^(w),—C(O)—R^(w), —C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w),—O—C(O)—N(R^(w))₂, —N(R^(w))—C(O)—OR^(w), —N(R^(w))—C(O)—N(R^(w))₂,—N(R^(w))—C(O)—R^(w), —N(R^(w))—S(O)—R^(w), —N(R^(w))—S(O)₂—R^(w),—N(R^(w))—S(O)—N(R^(w))₂, and —N(R^(w))—S(O)₂—N(R^(w))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(d),carbocyclyl, and heterocyclyl is optionally substituted with one or moregroups independently selected from oxo, halo, —NO₂, —N(R^(w))₂, —CN,—C(O)—N(R^(w))₂, —S(O)—N(R^(w))₂, —S(O)₂—N(R^(w))₂, —O—R^(w), —S—R^(w),—O—C(O)—R^(w), —C(O)—R^(w), —C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w),—C(O)—N(R^(w))₂, —N(R^(w))—C(O)—R^(w), —N(R^(w))—S(O)—R^(w),—N(R^(w))—S(O)₂—R^(w), C₂-C₆ alkenyl, R^(y), and C₁₋₆alkyl that isoptionally substituted with one or more groups independently selectedfrom oxo and halo;

each R^(c) is independently selected from hydrogen, halo, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein eachC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom halo, hydroxy, and C₁₋₆alkoxy;

each R^(d) is independently selected from hydrogen, halo, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein eachC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom halo, hydroxy, and C₁₋₆alkoxy;

each R^(v) is independently selected from hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein eachC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom oxo, cyano, nitro, halo, —N(R^(ax))₂, —OR^(ax), C₂-C₆ alkenyl,R^(ay), and C₁-C₆ alkyl that is optionally substituted with one or moregroups independently selected from oxo and halo; or two R^(v) are takentogether with the nitrogen to which they are attached to form aheterocyclyl that is optionally substituted with one or more groupsindependently selected from oxo, halo and C₁₋₃alkyl that is optionallysubstituted with one or more groups independently selected from oxo andhalo;

each R^(w) is independently selected from hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein eachC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom oxo, cyano, nitro, halo, —N(R^(x))₂, —OR^(x), C₂-C₆ alkenyl, R^(y),and C₁-C₆ alkyl that is optionally substituted with one or more groupsindependently selected from oxo and halo; or two R^(w) are takentogether with the nitrogen to which they are attached to form aheterocyclyl that is optionally substituted with one or more groupsindependently selected from oxo, halo and C₁₋₃alkyl that is optionallysubstituted with one or more groups independently selected from oxo andhalo;

each R^(x) is independently selected from hydrogen and C₁₋₆alkyl;

each R^(ax) is independently selected from hydrogen and C₁₋₆alkyl;

each R^(y) is aryl that is optionally substituted with one or moregroups independently selected from halo, hydroxyl, cyano, nitro, amino,—O—S(O)₂—R^(z), —OSi(R^(z))₃, and —O-(heterocyclyl);

each R^(ay) is aryl that is optionally substituted with one or moregroups independently selected from halo, hydroxyl, cyano, nitro, amino,—O—S(O)₂—R^(az), —OSi(R^(az))₃, and —O-(heterocyclyl);

each R^(z) is independently selected from C₁₋₆alkyl and aryl;

each R^(az) is independently selected from C₁₋₆alkyl and aryl;

each m is 1, 2, 3, 4, or 5; and

each n is 1, 2, 3, 4, or 5;

wherein the compound of formula (I) and formula (V) optionally comprisesone or more imaging isotopes;

wherein one or more carbon atoms of the compound of formula (I) andformula (V) is deuterated; and

wherein the compound of formula (V) is optionally substituted with oneor more groups R^(a). In some embodiments, formula (V) is substitutedwith one or more groups R^(a).

Another aspect includes a pharmaceutical composition comprising adeuterated compound as described herein, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable diluent orcarrier.

Another aspect includes a method for detecting neurofibrillary tanglesand/or senile plaques in an animal comprising administering a deuteratedcompound comprising an imaging isotope as described herein, or apharmaceutically acceptable salt thereof, to the animal, and measuringthe radioactive signal of the compound.

Another aspect includes a method of detecting a neurological disorderassociated with amyloid plaque and/or tau protein aggregation in ananimal comprising administering a deuterated compound comprising animaging isotope as described herein, or a pharmaceutically acceptablesalt thereof, to the animal, and measuring the radioactive signal of thecompound, which is associated with amyloid deposits and/or tau proteinaggregates.

Another aspect includes a method of detecting Alzheimer's diseaseassociated with amyloid plaque and/or tau protein aggregation in ananimal comprising administering a deuterated compound comprising animaging isotope as described herein, or a pharmaceutically acceptablesalt thereof, to the animal, and measuring the radioactive signal of thecompound associated with amyloid deposits and/or tau protein aggregates.

Another aspect includes a method of detecting Alzheimer's diseaseassociated with tau protein aggregation comprising administering adeuterated compound comprising an imaging isotope as described herein,or a pharmaceutically acceptable salt thereof, to the animal, andmeasuring the radioactive signal of the compound associated with tauprotein aggregates.

Another aspect includes a deuterated compound as described herein, or apharmaceutically acceptable salt thereof, for use in medical diagnosisor treatment.

Another aspect includes a deuterated compound as described herein, or apharmaceutically acceptable salt thereof, for use in detectingneurofibrillary tangles and/or senile plaques.

Another aspect includes a deuterated compound as described herein, or apharmaceutically acceptable salt thereof, for use in detecting aneurological disorder.

Another aspect includes a deuterated compound as described herein, or apharmaceutically acceptable salt thereof, for use in detectingAlzheimer's disease.

Another aspect includes the use of a deuterated compound as describedherein, or a pharmaceutically acceptable salt thereof, to prepare amedicament for detecting neurofibrillary tangles and/or senile plaquesin an animal.

Another aspect includes the use of a deuterated compound as describedherein, or a pharmaceutically acceptable salt thereof, to prepare amedicament for detecting a neurological disorder in an animal.

Another aspect includes the use of a deuterated compound as describedherein, or a pharmaceutically acceptable salt thereof, to prepare amedicament for detecting Alzheimer's disease in an animal.

Another aspect includes a method of detecting progressive supranuclearpalsy associated with amyloid plaque and/or tau protein aggregation inan animal, comprising administering a deuterated compound comprising animaging isotope as described herein, or a pharmaceutically acceptablesalt thereof, to the animal, and measuring the radioactive signal of thecompound associated with amyloid deposits and/or tau protein aggregates.

Another aspect includes a method of detecting progressive supranuclearpalsy associated with tau protein aggregation, comprising administeringa deuterated compound comprising an imaging isotope as described herein,or a pharmaceutically acceptable salt thereof, to the animal, andmeasuring the radioactive signal of the compound associated with tauprotein aggregates.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: Autoradiographic evaluation of binding properties of [A] and[A]-d2 using human brain tissues.

FIGS. 2A-2D: In vitro assessment of metabolic stability of [¹⁸F][A]-d2and [¹⁸F][A] using mouse and human liver microsomes. The formation of[¹⁸F]fluoride (2A and 2B) and amount of remaining parent compound weremeasured (2C and 2D) at 5, 15 and 45 min.

FIGS. 3A-3B: Human and mouse liver microsome assay performed withnon-radiolabeled [A] and [A]-d2 showed higher stability of [A]-d2 andslower metabolism of both compounds in presence of human livermicrosomes.

FIGS. 4A-4F: Pre-clinical PET imaging in mice from Example 6 below.

FIG. 5: Radio-HPLC chromatogram of purified [¹⁸F][A]-d2.

FIG. 6: Radio-HPLC chromatogram of purified [¹⁸F][A].

FIGS. 7A-7F: In vitro assessment of metabolic stability of [¹⁸F][A]-d2and [¹⁸F][A] (n=3) using human, rhesus or mouse liver microsomes. Theformation of [¹⁸F]fluoride (7A-7C) and amount of remaining parentcompound were measured (7D-7F) at 5, 15 and 45 min.

FIGS. 8A, 8B: [¹⁸F][A]-d2, [¹⁸F][A] or ¹⁸F T807 (370 MBq (10 mCi)) wasintravenous bolus injected into an anesthetized rhesus, and dynamic PETdata acquired over 240 minutes. Standard Uptake Values([Radioactivity]/(injected dose/body weight)) were measured in theindicated structures from the reconstructed PET data. Data was collectedfrom the same animal but on different days for each probe. [¹⁸F][A]-d2exhibited increased stability reflected by a reduction of skull uptakeof free fluoride.

FIG. 9: The temporal lobe [¹⁸F][A]-d2 standardized uptake value ratio(SUVR) vs. mean frame time in 3 subjects: 2 healthy controls (HC) andone suspected Alzheimer's patient (AD).

FIG. 10: Average [¹⁸F][A]-d2 SUVR (cerebellum gray as reference) in the90-120 min interval after tracer administration. Subjects 1-2, healthycontrols (HC). Subject 3, suspected AD patient.

DETAILED DESCRIPTION Compounds and Definitions

Definitions and terms are described in more detail below. Chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.

Unless otherwise stated, the a compounds include enantiomeric,diastereomeric and geometric (or conformational) isomeric forms of agiven structure. For example, the R and S configurations for eachasymmetric center, Z and E double bond isomers, Z and E conformationalisomers, single stereochemical isomers, as well as enantiomeric,diastereomeric, and geometric (or conformational) mixtures are included.Unless otherwise stated, all tautomeric forms of structures depictedherein are included. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds, wherein the independent replacement or enrichment of one ormore hydrogen by deuterium or tritium, carbon by ¹³C- or ¹⁴C carbon,nitrogen by a ¹⁵N nitrogen, sulfur by a ³³S, ³⁴S or ³⁶S sulfur, oroxygen by a ¹⁷O or ¹⁸O oxygen are included. Such compounds are useful,for example, as analytical tools, as probes in biological assays, or astherapeutic agents.

Where a particular enantiomer is described, it may, in certainembodiments be provided substantially free of the correspondingenantiomer, and may also be referred to as “optically enriched.”“Optically-enriched,” as used herein, means that the mixture ofenantiomers is made up of a significantly greater proportion of oneenantiomer, and may be described by enantiomeric excess (ee %). Incertain embodiments, the mixture of enantiomers is made up of at leastabout 90% by weight of a given enantiomer (about 90% ee). In otherembodiments, the mixture of enantiomers is made up of at least about95%, 98% or 99% by weight of a given enantiomer (about 95%, 98% or 99%ee). Enantiomers and diastereomers may be isolated from racemic mixturesby any method known to those skilled in the art, includingrecrystallization from solvents in which one stereoisomer is moresoluble than the other, chiral high pressure liquid chromatography(HPLC), supercritical fluid chromatography (SFC), the formation andcrystallization of chiral salts, which are then separated by any of theabove methods, or prepared by asymmetric syntheses and optionallyfurther enriched. See, for example, Jacques et al., Enantiomers,Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen,et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry ofCarbon Compounds (McGrawHill, N.Y., 1962); Wilen, S. H. Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972).

The term “heteroatom” means any atom independently selected from an atomother than carbon or hydrogen, for example, one or more of oxygen,sulfur, nitrogen, phosphorus or silicon (including any oxidized form ofnitrogen, sulfur, phosphorus or silicon; and the quaternized form of anynitrogen).

The terms “halo” and “halogen” as used herein refer to an atom selectedfrom fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br)and iodine (iodo, —I).

The term “oxo” refers to ═O or (═O)₂.

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The term “carbocyclyl” used alone or as part of a larger moiety, refersto a saturated, partially unsaturated, or aromatic ring system having 3to 20 carbon atoms. In one embodiment, carbocyclyl includes 3 to 12carbon atoms (C₃-C₁₂). In another embodiment, carbocyclyl includesC₃-C₈, C₃-C₁₀ or C₅-C₁₀. In other embodiment, carbocyclyl, as amonocycle, includes C₃-C₈, C₃-C₆ or C₅-C₆. In another embodiment,carbocyclyl, as a bicycle, includes C₇-C₁₂. In another embodiment,carbocyclyl, as a spiro system, includes C₅-C₁₂. Examples of monocycliccarbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,perdeuteriocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl,1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecyl, phenyl, and cyclododecyl; bicycliccarbocyclyls having 7 to 12 ring atoms include [4,3], [4,4], [4,5],[5,5], [5,6] or [6,6] ring systems, for example bicyclo[2.2.1]heptanyl,bicyclo[2.2.2]octanyl, naphthalenyl, and bicyclo[3.2.2]nonanyl; andspiro carbocyclyls include spiro[2.2]pentanyl, spiro[2.3]hexanyl,spiro[2.4]heptanyl, spiro[2.5]octanyl and spiro[4.5]decanyl. The termcarbocyclyl includes aryl ring systems as defined herein. The termcarbocycyl also includes cycloalkyl rings (e.g., saturated or partiallyunsaturated mono-, bi-, or spiro-carbocycles).

The term “alkyl,” as used herein, refers to a saturated linear orbranched-chain monovalent hydrocarbon radical. In one embodiment, thealkyl radical is one to eighteen carbon atoms (C₁-C₁₈). In otherembodiments, the alkyl radical is C₀-C₆, C₀-C₅, C₀-C₃, C₁-C₁₂, C₁-C₁₀,C₁-C₈, C₁-C₆, C₁-C₅, C₁-C₄ or C₁-C₃. C₀ alkyl refers to a bond. Examplesof alkyl groups include methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl(n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂),1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu,i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, heptyl, octyl, nonyl, decyl,undecyl and dodecyl.

The term “alkenyl,” as used herein, denotes a linear or branched-chainmonovalent hydrocarbon radical with at least one carbon-carbon doublebond. An alkenyl includes radicals having “cis” and “trans”orientations, or alternatively, “E” and “Z” orientations. In oneexample, the alkenyl radical is two to eighteen carbon atoms (C₂-C₁₈).In other examples, the alkenyl radical is C₂-C₁₂, C₂-C₈, C₂-C₆ or C₂-C₃.Examples include, but are not limited to, ethenyl or vinyl (—CH═CH₂),prop-1-enyl (—CH═CHCH₃), prop-2-enyl (—CH₂CH═CH₂), 2-methylprop-1-enyl,but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl,2-methylbuta-1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyland hexa-1,3-dienyl.

The term “alkynyl,” as used herein, refers to a linear or branchedmonovalent hydrocarbon radical with at least one carbon-carbon triplebond. In one example, the alkynyl radical is two to eighteen carbonatoms (C₂-C₁₈). In other examples, the alkynyl radical is C₂-C₁₂,C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₃. Examples include, but are not limited to,ethynyl (—C≡CH), prop-1-ynyl (—C≡CCH₃), prop-2-ynyl (propargyl,—CH₂C≡CH), but-1-ynyl, but-2-ynyl and but-3-ynyl.

The term “alkoxy” refers to a linear or branched monovalent radicalrepresented by the formula —OR in which R is alkyl, alkenyl, alkynyl orcarbocycyl. Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy,and cyclopropoxy.

The term “haloalkyl,” as used herein, refers to an alkyl as definedherein that is substituted with one or more (e.g., 1, 2, 3, or 4) halogroups.

The term “aryl” used alone or as part of a larger moiety as in“arylalkyl”, “arylalkoxy”, or “aryloxyalkyl”, refers to a monocyclic,bicyclic or tricyclic, carbon ring system, that includes fused rings,wherein at least one ring in the system is aromatic. The term “aryl” maybe used interchangeably with the term “aryl ring”. In one embodiment,aryl includes groups having 6-18 carbon atoms. In another embodiment,aryl includes groups having 6-10 carbon atoms. Examples of aryl groupsinclude phenyl, naphthyl, anthracyl, biphenyl, phenanthrenyl,naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl,2,3-dihydro-1H-indenyl, and the like, which may be substituted orindependently substituted by one or more substituents described herein.A particular aryl is phenyl. In another embodiment aryl includes an arylring fused to one or more carbocyclic rings, such as indanyl,phthalimidyl, naphthimidyl, phenantriidinyl, or tetrahydronaphthyl, andthe like, where the radical or point of attachment is on an aromaticring.

The term “heteroaryl” used alone or as part of a larger moiety, e.g.,“heteroarylalkyl”, or “heteroarylalkoxy”, refers to a monocyclic,bicyclic or tricyclic ring system having 5 to 14 ring atoms, wherein atleast one ring is aromatic and contains at least one heteroatom. In oneembodiment, heteroaryl includes 4-6 membered monocyclic aromatic groupswhere one or more ring atoms is nitrogen, sulfur or oxygen that isindependently optionally substituted. In another embodiment, heteroarylincludes 5-6 membered monocyclic aromatic groups where one or more ringatoms is nitrogen, sulfur or oxygen that is independently optionallysubstituted. In another embodiment, heteroaryl includes bicyclic ortricyclic aromatic groups where one or more ring atoms (e.g., 1, 2, 3,4, 5, 6, 7, or 8) is nitrogen, sulfur or oxygen that is independentlyoptionally substituted. Example heteroaryl groups include thienyl,furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl,thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl,imidazol[1,2-a]pyrimidinyl, purinyl, benzoxazolyl, benzofuryl,benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl,indolyl, 1,3-oxazol-2-yl, oxadiazol-5-yl, 1H-tetrazol-5-yl,1,2,3-triazol-5-yl, and pyrid-2-yl N-oxide. The terms “heteroaryl” alsoincludes groups in which a heteroaryl is fused to one or more aryl,carbocyclyl, or heterocyclyl rings, where the radical or point ofattachment is on the heteroaryl ring. Nonlimiting examples includeindolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl,indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl andpyrido[2,3-b]-1,4-oxazin-3(4H)-onyl. A heteroaryl group may be mono-,bi- or tri-cyclic.

As used herein, the term “heterocyclyl” refers to a “carbocyclyl” asdefined herein, wherein one or more (e.g., 1, 2, 3, or 4) carbon atomshave been replaced with a heteroatom (e.g., O, N, or S). In someembodiments, a heterocyclyl refers to a saturated ring system, such as a3 to 12 membered saturated heterocyclyl ring system. In someembodiments, a heterocyclyl refers to a heteroaryl ring system, such asa 5 to 14 membered heteroaryl ring system. A heterocyclyl can optionallybe substituted with one or more substituents independently selected fromthose defined herein. In one embodiment, heterocyclyl includes 5-6membered monocyclic cyclic groups where one or more ring atoms isnitrogen, sulfur or oxygen (e.g., 1, 2, 3 or 4) that is independentlyoptionally substituted. In another embodiment, heterocyclyl includesbicyclic or tricyclic groups where one or more ring atoms (e.g., 1, 2,3, 4, 5, 6, 7, or 8) is nitrogen, sulfur or oxygen that is independentlyoptionally substituted.

In one example, heterocyclyl includes 3-12 ring atoms and includesmonocycles, bicycles, tricycles and spiro ring systems, wherein the ringatoms are carbon, and one to five ring atoms is a heteroatom selectedfrom nitrogen, sulfur or oxygen, which is independently optionallysubstituted by one or more groups. In one example, heterocyclyl includes1 to 4 heteroatoms. In another example, heterocyclyl includes 3- to7-membered monocycles having one or more heteroatoms selected fromnitrogen, sulfur or oxygen. In another example, heterocyclyl includes 4-to 6-membered monocycles having one or more heteroatoms selected fromnitrogen, sulfur or oxygen. In another example, heterocyclyl includes3-membered monocycles. In another example, heterocyclyl includes4-membered monocycles. In another example, heterocyclyl includes 5-6membered monocycles. In one example, the heterocyclyl group includes 0to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally beoxidized (e.g., NO, SO, SO₂), and any nitrogen heteroatom may optionallybe quaternized (e.g., [NR₄]⁺Cl⁻, [NR₄]⁺OH⁻). Example heterocyclylsinclude oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl,thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl,dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl,tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl,tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl,oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl,azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl,1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl,tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl,1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl,4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl,4,5,6,7-tetrahydrobenzo[d]imidazolyl,1,6-dihydroimidazol[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, oxazinyl,thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl,thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl,dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl,pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl,piperazindionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl,3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl,3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl,azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl,8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl,8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane,azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl,1-azaspiro[4.5]decan-2-only, azaspiro[5.5]undecanyl, tetrahydroindolyl,octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, and1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclylscontaining a sulfur or oxygen atom and one to three nitrogen atoms arethiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide,thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl,oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl. Example 5-membered ringheterocyclyls containing 2 to 4 nitrogen atoms include imidazolyl, suchas imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl;1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as1H-tetrazol-5-yl. Example benzo-fused 5-membered heterocyclyls arebenzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl. Example6-membered heterocyclyls contain one to three nitrogen atoms andoptionally a sulfur or oxygen atom, for example pyridyl, such aspyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yland pyrimid-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, andpyrazinyl. The pyridine N-oxides and pyridazine N-oxides and thepyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the1,3,4-triazin-2-yl groups, are other example heterocyclyl groups.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond between ring atoms butthe ring moiety is not aromatic.

“Pharmaceutically acceptable salts” include both acid and base additionsalts. It is to be understood that when a compound or Example herein isshown as a specific salt, the corresponding free-base, as well as othersalts of the corresponding free-base (including pharmaceuticallyacceptable salts of the corresponding free-base) are contemplated.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases and which are not biologically or otherwise undesirable, formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like,and organic acids may be selected from aliphatic, cycloaliphatic,aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes oforganic acids such as formic acid, acetic acid, propionic acid, glycolicacid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid,maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid,citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilicacid, benzoic acid, cinnamic acid, mandelic acid, embonic acid,phenylacetic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, salicyclic acid and thelike.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Particularly base addition salts are the ammonium, potassium,sodium, calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases includes salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particular organicnon-toxic bases are isopropylamine, diethylamine, ethanolamine,tromethamine, dicyclohexylamine, choline, and caffeine.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

As between chemical names and structures shown, if there are anydiscrepancies, the structure prevails.

Throughout this application, the term “about” is used to indicate that avalue includes the standard deviation of error for the device and/ormethod being employed to determine the value.

As used herein, “a” or “an” means one or more, unless clearly indicatedotherwise. As used herein, “another” means at least a second or more.

Imaging Isotopes and Imaging

Diagnostic techniques in nuclear medicine use radioactive tracers whichemit gamma rays from within the body. These tracers are generallyshort-lived isotopes linked to chemical compounds which permit specificphysiological processes to be scrutinized. They can be given byinjection, inhalation or orally. The first type is where single photonsare detected by a gamma camera which can view organs from many differentangles. The camera builds up an image from the points from whichradiation is emitted; this image is enhanced by a computer and viewed bya physician on a monitor for indications of abnormal conditions.

Positron Emission Tomography (PET) is a precise and sophisticatedtechnique using isotopes produced in a cyclotron. A positron-emittingradionuclide is introduced, usually by injection, and accumulates in thetarget tissue. As it decays it emits a positron, which promptly combineswith a nearby electron resulting in the simultaneous emission of twoidentifiable gamma rays in opposite directions. These are detected by aPET camera and give a very precise indication of their origin. PET'smost important clinical role is in oncology, with fluorine-18 as thetracer, since it has proven to be the most accurate non-invasive methodof detecting and evaluating most cancers. It is also well used incardiac and brain imaging.

A number of medical diagnostic procedures, including PET and SPECT,utilize radiolabeled compounds and are well known in the art. PET andSPECT are very sensitive techniques and require small quantities ofradiolabeled compounds, called tracers. The labeled compounds aretransported, accumulated and converted in vivo in a similar manner asthe corresponding non-radioactively labeled compound. Tracers, orprobes, can be radiolabeled with a radionuclide useful for PET imaging,such as ¹¹C, ¹³N, ¹⁵O, ¹⁸F, ⁶⁴Cu, and ¹²⁴I, or with a radionuclideuseful for SPECT imaging, such as ⁹⁹Tc, ⁷⁷Br, ⁶¹Cu, ¹⁵³Gd, ¹²³I, ¹²⁵I,¹³¹I and ³²P. These are examples of “imaging isotopes,” as that term isused herein.

PET creates images based on the distribution of molecular imagingtracers carrying positron-emitting isotopes in the tissue of thepatient. The PET method has the potential to detect malfunction on acellular level in the investigated tissues or organs. PET has been usedin clinical oncology, such as for the imaging of tumors and metastases,and has been used for diagnosis of certain brain diseases, as well asmapping brain and heart function. Similarly, SPECT can be used tocomplement any gamma imaging study, where a true 3D representation canbe helpful, for example, imaging tumor, infection (leukocyte), thyroidor bones.

According to another embodiment, the present invention is also directedat a method of imaging amyloid deposits and NTFs. When the compounds ofthis invention are used as imaging agents, they are labeled with one ormore suitable imaging isotopes (e.g., radioactive isotopes, radiolabelsor radioactive labels), for example, radioactive halogens, such as ¹⁸Fand/or with one or more radioactive metals.

Regarding radiohalogens, ¹²⁵I isotopes are useful for laboratory testingbut they will generally not useful for diagnostic purposes because ofthe relatively long half-life (60 days) and low gamma-emission (30-65keV) of ¹²⁵I. The isotope ¹²³I has a half-life of thirteen hours andgamma energy of 159 keV, and it is therefore typical that labeling ofligands to be used for diagnostic purposes would be with this isotope orwith ¹⁸F (half-life of 2 hours). Other imaging isotopes which may beused include ¹³¹I, ⁷⁷Br and ⁷⁶Br.

In another embodiment, compounds of the present invention contain aradioactive isotope of carbon as the radiolabel. This refers to acompound that comprises one or more radioactive carbon atoms, preferably¹¹C, with a specific activity above that of the background level forthat atom. It is well known that naturally occurring elements arepresent in the form of varying isotopes, some of which are radioactive.The radioactivity of the naturally occurring elements is a result of thenatural distribution or abundance of these isotopes, and is commonlyreferred to as a background level. The carbon labeled compounds of thepresent invention have a specific activity that is higher than thenatural abundance, and therefore above the background level. The carbonlabeled compositions of the present invention can be used for tracing,imaging, radiotherapy, and the like.

Those skilled in the art are familiar with the various ways to detectlabeled compounds for imaging purposes. For example, positron emissiontomography (PET) or single photon emission computed tomography (SPECT)can be used to detect radiolabeled compounds. The label that isintroduced into the compound can depend on the detection method desired.Those skilled in the art are familiar with PET detection of apositron-emitting atom, such as ¹⁸F. The present invention is alsodirected to specific compounds described herein where the ¹⁸F atom isreplaced with a non-radiolabeled fluorine atom. Those skilled in the artare familiar with SPECT detection of a photon-emitting atom, such as¹²³I or ^(99m)Tc.

The radioactive diagnostic or detection agent should have sufficientradioactivity and radioactivity concentration which can assure reliablediagnosis and detection. The desired level of radioactivity can beattained by the methods provided herein for preparing compounds. Theimaging of amyloid deposits and NTFs can also be carried outquantitatively so that the amount of amyloid deposits and NTFs can bedetermined.

Typically, a prerequisite for an in vivo imaging agent of the brain isthe ability to cross the intact blood-brain barrier. In a first step ofa method of imaging, a labeled compound is introduced into a tissue or apatient in a detectable quantity. The compound is typically part of apharmaceutical composition and is administered to the tissue or thepatient by methods well known to those skilled in the art. Typically,administration is intravenously.

In other embodiments of the invention, the labeled compound isintroduced into a patient in a detectable quantity and after sufficienttime has passed for the compound to become associated with amyloiddeposits and/or tau proteins, the labeled compound is detectednoninvasively. In another embodiment of the invention, a labeledcompound is introduced into a patient, sufficient time is allowed forthe compound to become associated with amyloid deposits, and then asample of tissue from the patient is removed and the labeled compound inthe tissue is detected apart from the patient. In another embodiment ofthe invention, a tissue sample is removed from a patient and a labeledcompound is introduced into the tissue sample. After a sufficient amountof time for the compound to become bound to amyloid deposits and/or tauproteins, the compound is detected.

A detectable quantity is a quantity of labeled compound necessary to bedetected by the detection method chosen. The amount of a labeledcompound to be introduced into a patient in order to provide fordetection can readily be determined by those skilled in the art. Forexample, increasing amounts of the labeled compound can be given to apatient until the compound is detected by the detection method ofchoice. A label is introduced into the compounds to provide fordetection of the compounds.

The amount of time necessary can easily be determined by introducing adetectable amount of a labeled compound into a patient and thendetecting the labeled compound at various times after administration.

The administration of the labeled compound to a patient can be by ageneral or local administration route. For example, the labeled compoundmay be administered to the patient such that it is delivered throughoutthe body. Alternatively, the labeled compound can be administered to aspecific organ or tissue of interest. For example, it is desirable tolocate and quantitate amyloid deposits in the brain in order to diagnoseor track the progress of Alzheimer's disease in a patient.

One or more imaging isotopes can be incorporated into a compound offormula (I) by replacing one or more atoms (e.g., hydrogen or carbonatoms) in the compound of formula (I) or formula (V) with an imagingisotope. The incorporation of an imaging isotope can be carried outusing known techniques. For example, techniques may be based onnucleophilic or electrophilic ¹⁸F-fluorination of suitable precursors asreviewed, for example, in Medicinal Chemistry Approaches to PersonalizedMedicine (Lackey, Roth Eds), Chapter 12 (Wiley-VCH, ISBN978-3-527-33394-3). See also U.S. Patent Application No. 2011/0182812,incorporated herein by reference in its entirety.

Deuterated

The term “deuterated” means enriched in deuterium above its naturalabundance at one or more positions of a compound. When a particularposition, for example, a carbon atom, is deuterated, it is understoodthat the abundance of deuterium at that position is substantiallygreater than the natural abundance of deuterium, which is 0.015%. Adeuterated position typically has a minimum isotopic enrichment factorof at least 3000 (45% deuterium incorporation).

The term “isotopic enrichment factor” as used herein means the ratiobetween the isotopic abundance and the natural abundance of a specifiedisotope. In certain embodiments, a compound has an isotopic enrichmentfactor of at least 3500 (52.5% deuterium incorporation) at a givendeuterated atom, at least 4000 (60% deuterium incorporation), at least4500 (67.5% deuterium incorporation), at least 5000 (75% deuteriumincorporation), at least 5500 (82.5% deuterium incorporation), at least6000 (90% deuterium incorporation), at least 6333.3 (95% deuteriumincorporation), at least 6466.7 (97% deuterium incorporation), at least6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuteriumincorporation). In some embodiments, 100% deuterium incorporation isachieved.

It is to be understood that a deuterated compound contains one or moredeuterium atoms. For example, a deuterated compound may contain just onedeuterium. In some embodiments, a deuterated compound contains just twodeuteriums. In some embodiments, a deuterated compound contains onlythree deuteriums. In some embodiments, a deuterated compound containsfour deuteriums. In some embodiments, a deuterated compound contains 1,2, 3, or 4 deuteriums, or any range derivable therein.

Deuterium can be incorporated into a compound of formula (I) using avariety of known reagents and synthetic techniques. For example,deuterium can be incorporated into a compound of formula (I) usingLiAlD₄. It can also be incorporated into a compound of formula (I) suchas through reduction, catalytic hydrogenation or isotopic exchange usingappropriate deuterated reagents such as deuterides, D₂ and D₂O.

Exemplary Values

In certain embodiments the compound is a compound of formula (I) or asalt thereof.

In certain embodiments R¹ is a 6-membered heteroaryl ring.

In certain embodiments R¹ is:

wherein:

X₁, X₂, X₃, and X₄ are each independently CH or N; and

wherein R¹ is optionally substituted with one or more groups R^(a).

In certain embodiments R¹ is phenyl, pyridyl, or pyrimidyl.

In certain embodiments R¹ is a 9- or 10-membered bicyclic heteroarylring.

In certain embodiments R¹ is a 9- or 10-membered bicyclic heteroarylring that comprises one or more nitrogens.

In certain embodiments R¹ is a 9- or 10-membered bicyclic heteroarylring that comprises two or more nitrogens.

In certain embodiments R¹ is a 9- or 10-membered bicyclic heteroarylring that comprises one or more nitrogens and one or more oxygens.

In certain embodiments R¹ is:

wherein:

X₅, X₆, X₇, and X₈ are each independently CH or N;

X₉ is CH₂, NH, O, or S; and

Y₁ is CH, or N;

wherein R¹ is optionally substituted with one or more groups R^(a).

In certain embodiments R¹ is:

wherein:

X₅, X₆, X₇, and X₈ are each independently CH or N; and

X₉ is CH₂, NH, O, or S;

wherein R¹ is optionally substituted with one or more groups R^(a).

In certain embodiments R¹ is:

wherein:

X₈ is CH or N; and X₉ is CH₂, NH, O, or S; wherein R¹ is optionallysubstituted with one or more groups R^(a).

In certain embodiments X₉ is CH₂.

In certain embodiments X₉ is O.

In certain embodiments X₉ is S.

In certain embodiments R¹ is:

wherein:

X₂₀-X₂₇ are each independently CH or N;

wherein R¹ is optionally substituted with one or more groups R^(a).

In certain embodiments R¹ is:

wherein R¹ is optionally substituted with one or more groups R^(a).

In certain embodiments R¹ is a 12-13 membered tricyclic heterocyclylthat comprises one or more nitrogens.

In certain embodiments R¹ is a 12-13 membered tricyclic heterocyclylthat comprises two or more nitrogens.

In certain embodiments R¹ is a 12-13 membered tricyclic heterocyclylthat comprises three or more nitrogens.

In certain embodiments R¹ is:

wherein:

each X₁₀-X₁₇ is independently CH or N; and

X₁₈ is CH₂, NH, O, or S;

wherein R¹ is optionally substituted with one or more groups R^(a).

In certain embodiments R¹ is:

wherein:

each X₁₀-X₁₇ is independently CH or N;

X₁₈ is CH or N; and

X₁₉ is CH or N;

wherein R¹ is optionally substituted with one or more groups R^(a).

In certain embodiments R¹ is:

wherein:

each X₁₄-X₁₇ is independently CH or N;

X₁₈ is CH or N; and

X₁₉ is CH or N;

wherein R¹ is optionally substituted with one or more groups R^(a).

In certain embodiments R¹ is:

and is optionally substituted with one or more groups R^(a).

In certain embodiments R¹ is:

and is optionally substituted with one or more groups R^(a).

In certain embodiments R¹ is:

wherein:

each X₃₀-X₃₇ is independently CH or N; and

X₃₈ is CH₂, NH, O, or S;

wherein R¹ is optionally substituted with one or more groups R^(a).

In certain embodiments A is absent.

In certain embodiments A is ethynyl;

In certain embodiments R² is a 6-membered carbocyclyl that is optionallysubstituted with one or more groups R^(b).

In certain embodiments R² is cyclohexyl or phenyl, which cyclohexyl andphenyl is optionally substituted with one or more groups R^(b).

In certain embodiments R² is pyrrolyl, thiophenyl, imidazolyl,thiazolyl, oxazolyl, pyrazolyl, isoxazolyl, isothiazolyl, morpholinyl,piperidinyl, piperazinyl, pyrrolidinyl, pyridinyl, pyrimidinyl,pyrazinyl, 3-azabicyclo[3.1.0]hexanyl, or pyridazinyl, which R² isoptionally substituted with one or more groups R^(b).

In certain embodiments the compound is a compound of formula (V), or asalt thereof.

In certain embodiments the compound is a compound of formula (Va):

or a salt thereof, wherein the compound of formula (Va) is substitutedwith one or more groups R^(a).

In certain embodiments the compound comprises an imaging isotope.

In certain embodiments the imaging isotope is ¹⁸F.

In certain embodiments the compound is a compound having the formula(Ia):

or a salt thereof, wherein:

R² is 6-membered carbocyclyl or a 5- or 6-membered heterocyclyl, whichcarbocyclyl and heterocyclyl is optionally substituted with one or moregroups R^(b);

each R^(b) is independently selected from C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(d), carbocyclyl, heterocyclyl, —F, —Cl,—Br, —I, —NO₂, —N(R^(w))₂, —CN, —C(O)—N(R^(w))₂, —O—C(O)—R^(w),—C(O)—R^(w), and —C(O)—O—R^(w), wherein any C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(d), carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom oxo, halo, —O—R^(w), —O—C(O)—R^(w), —C(O)—R^(w), —C(O)—O—R^(w),—C(O)—N(R^(w))₂, and —N(R^(w))—C(O)—R^(w).

In certain embodiments the compound is a compound having formula (Ia):

or a salt thereof, wherein:

R² is piperidinyl or 3-azabicyclo[3.1.0]hexanyl, which piperidinyl and3-azabicyclo[3.1.0]hexanyl is optionally substituted with one or moregroups R^(b); and each R^(b) is independently selected from C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(d), carbocyclyl,heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(w))₂, —CN, —C(O)—N(R^(w))₂,—O—R^(w), —O—C(O)—R^(w), —C(O)—R^(w), and —C(O)—O—R^(w), wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(d),carbocyclyl, and heterocyclyl is optionally substituted with one or moregroups independently selected from oxo, halo, —O—R^(w), —O—C(O)—R^(w),—C(O)—R^(w), —C(O)—O—R^(w), —C(O)—N(R^(w))₂, and —N(R^(w))—C(O)—R^(w).

In certain embodiments the compound is a compound having formula (Ib):

or a salt thereof, wherein:

R^(b) is deuterated and is selected from C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(d), carbocyclyl, heterocyclyl,—N(R^(w))₂, —C(O)—N(R^(w))₂, —O—C(O)—R^(w), —C(O)—R^(w), and—C(O)—O—R^(w), wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,—(O—CH₂—CH₂)_(m)—R^(d), carbocyclyl, and heterocyclyl is optionallysubstituted with one or more groups independently selected from oxo,halo, —O—R^(w), —O—C(O)—R^(w), —C(O)—R^(w), —C(O)—O—R^(w),—C(O)—N(R^(w))₂, and —N(R^(w))—C(O)—R^(w); and

R^(b) comprises one or more imaging isotopes.

In certain embodiments the compound is a compound having formula (Ic):

or a salt thereof, wherein:

R^(b) is deuterated and is selected from C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(d), carbocyclyl, heterocyclyl,—N(R^(w))₂, —C(O)—N(R^(w))₂, —O—C(O)—R^(w), —C(O)—R^(w), and—C(O)—O—R^(w), wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,—(O—CH₂—CH₂)_(m)—R^(d), carbocyclyl, and heterocyclyl is optionallysubstituted with one or more groups independently selected from oxo,halo, —O—R^(w), —O—C(O)—R^(w), —C(O)—R^(w), —C(O)—O—R^(w),—C(O)—N(R^(w))₂, and —N(R^(w))—C(O)—R^(w); and

R^(b) comprises one or more imaging isotopes.

In certain embodiments the compound is a compound having formula (Id):

or a salt thereof, wherein:

R^(b) is deuterated and is selected from C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(d), carbocyclyl, heterocyclyl,—N(R^(w))₂, —C(O)—N(R^(w))₂, —O—C(O)—R^(w), —C(O)—R^(w), and—C(O)—O—R^(w), wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,—(O—CH₂—CH₂)_(m)—R^(d), carbocyclyl, and heterocyclyl is optionallysubstituted with one or more groups independently selected from oxo,halo, —O—R^(w), —O—C(O)—R^(w), —C(O)—R^(w), —C(O)—O—R^(w),—C(O)—N(R^(w))₂, and —N(R^(w))—C(O)—R^(w); and

R^(b) comprises one or more imaging isotopes.

In certain embodiments each R^(a) is independently selected fromC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, and —O—R^(v); and each R^(v) isindependently selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionallysubstituted with one or more groups independently selected —OR^(ax).

In certain embodiments each R^(a) is independently selected from—O—R^(v); and each R^(v) is independently selected from hydrogen,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, and carbocyclyl.

In certain embodiments each R^(a) is independently selected from —O—CH₃.

In certain embodiments each R^(b) is independently selected fromC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, and —O—R^(w), wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, and C₂₋₆alkynyl, is optionally substituted withone or more groups independently selected from —O—R^(w); and each R^(w)is independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionallysubstituted with one or more groups independently selected from —OR^(x);wherein at least one R^(b) is deuterated and comprises one or moreimaging isotopes.

In certain embodiments each R^(b) is C₁₋₆alkyl that is optionallysubstituted with one or more groups independently selected from—O—R^(w); and each R^(w) is independently selected from C₁₋₆alkyl;wherein at least one R^(b) is deuterated and comprises one or moreimaging isotopes.

In certain embodiments R^(b) is a C₁₋₆alkyl group that comprises one ormore imaging isotopes.

In certain embodiments R^(b) is a C₁₋₆alkyl group that comprises animaging isotope ¹⁸F.

In certain embodiments the compound comprises a carbon atom that is bothdeuterated and covalently bonded to an imaging isotope.

In certain embodiments R^(b) is —CH₂-*CD₂-¹⁸F, wherein the carbonmarked * is deuterated.

In certain embodiments R^(b) is CH₂-*CD₂-¹⁸F, wherein the carbonmarked * has a deuterium isotopic enrichment factor of at least 3500.

In certain embodiments R^(b) is CH₂-*CD₂-¹⁸F, wherein the carbonmarked * has a deuterium isotopic enrichment factor of at least 6000.

In certain embodiments R^(b) is CH₂— CH₂—O-*CD₂-*CD₂-¹⁸F, wherein eachcarbon marked * is deuterated.

In certain embodiments R^(b) is CH₂— CH₂—O-*CD₂-*CD₂-¹⁸F, wherein eachcarbon marked * has a deuterium isotopic enrichment factor of at least3500.

In certain embodiments R^(b) is CH₂— CH₂—O-*CD₂-*CD₂-¹⁸F, wherein eachcarbon marked * has a deuterium isotopic enrichment factor of at least6000.

In certain embodiments the compound is a compound having the formula(Ie):

wherein the carbon marked * has a deuterium isotopic enrichment factorof at least 3500. In certain embodiments the carbon marked * has adeuterium isotopic enrichment factor of at least 4000. In certainembodiments the carbon marked * has a deuterium isotopic enrichmentfactor of at least 4500. In certain embodiments the carbon marked * hasa deuterium isotopic enrichment factor of at least 5000. In certainembodiments the carbon marked * has a deuterium isotopic enrichmentfactor of at least 5500. In certain embodiments the carbon marked * hasa deuterium isotopic enrichment factor of at least 6000. In certainembodiments the carbon marked * has a deuterium isotopic enrichmentfactor of at least 6333.3. In certain embodiments the carbon marked *has a deuterium isotopic enrichment factor of at least 6466.7. Incertain embodiments the carbon marked * has a deuterium isotopicenrichment factor of at least 6600. In certain embodiments the carbonmarked * has a deuterium isotopic enrichment factor of at least 6633.3.In some embodiments, 100% deuterium incorporation is achieved withrespect to the carbon marked * in the compound of formula (Ie).

In certain embodiments the compound is a compound having the formula:

or a salt thereof. In certain embodiments the compound is a compoundselected from:

and salts thereof.

R¹ can be attached to the remainder of a compound of formula (I) throughany synthetically feasible position. For example, when R¹ has one of thefollowing values, it can be attached to the remainder of a compound offormula (I) through any synthetically feasible position:

For example, in one embodiment, a hydrogen atom can be removed from acarbon or nitrogen atom in R¹ to provide an open valence that can formthe covalent bond with the remainder of a compound of formula (I).

Indications

Compounds of the present invention may be used in a variety of contexts,such as imaging and detection contexts. In certain embodiments, thecompound is introduced into patients who suffer from or are at risk ofdeveloping a neurological disorder. In certain embodiments, theneurological disorder is associated with the development of amyloidplaques and/or tau protein aggregates and/or NFTs.

A “neurological disorder” as used herein refers to a disease or disorderwhich affects the CNS and/or which has an etiology in the CNS. ExemplaryCNS diseases or disorders include, but are not limited to, neuropathy,amyloidosis, cancer, an ocular disease or disorder, viral or microbialinfection, inflammation, ischemia, neurodegenerative disease, seizure,behavioral disorders, and a lysosomal storage disease. For the purposesof this application, the CNS will be understood to include the eye,which is normally sequestered from the rest of the body by theblood-retina barrier. Specific examples of neurological disordersinclude, but are not limited to, neurodegenerative diseases including,but not limited to, Lewy body disease, postpoliomyelitis syndrome,Shy-Draeger syndrome, olivopontocerebellar atrophy, Parkinson's disease,multiple system atrophy, striatonigral degeneration, prion diseases(including, but not limited to, bovine spongiform encephalopathy,scrapie, Creutzfeldt-Jakob syndrome, kuru,Gerstmann-Straussler-Scheinker disease, chronic wasting disease, andfatal familial insomnia), bulbar palsy, motor neuron disease, nervoussystem heterodegenerative disorders (including, but not limited to,Canavan disease, Huntington's disease, neuronal ceroid-lipofuscinosis,Alexander's disease, Tourette's syndrome, Menkes kinky hair syndrome,Cockayne syndrome, Halervorden-Spatz syndrome, lafora disease, Rettsyndrome, hepatolenticular degeneration, Lesch-Nyhan syndrome, andUnverricht-Lundborg syndrome), dementia (including, but not limited to,Pick's disease, and spinocerebellar ataxia), and cancer (e.g., of theCNS, including brain metastases resulting from cancer elsewhere in thebody). Tauopathies are also encompassed by the term “neurologicaldisorder” and refer to tau-related disorders or conditions that mayoverlap with one or more of the conditions noted above. Non-limitingexamples of tauopathies include, but are not limited to, Alzheimer'sdisease, progressive supranuclear palsy, corticobasal degeneration,Pick's disease, stroke, aging, traumatic brain injury, and mildcognitive impairment.

Formulation and Administration

Another aspect includes a pharmaceutical composition comprising acompound of formula (I) or a pharmaceutically acceptable salt thereof.In one embodiment, the composition further comprises a pharmaceuticallyacceptable carrier or vehicle. In certain embodiments, the compositionis formulated for administration to a patient in need thereof.

The term “patient” or “individual” as used herein, refers to an animal,such as a mammal, such as a human. In one embodiment, patient orindividual refers to a rodent (e.g., mouse or rat), a dog, or a human.

The term “pharmaceutically acceptable carrier or vehicle” refers to anon-toxic carrier or vehicle that does not destroy the pharmacologicalactivity of the compound with which it is formulated. Pharmaceuticallyacceptable carriers or vehicles that may be used in the compositions ofthis invention include, but are not limited to, water, salts, andethanol

Compositions comprising a compound or salt thereof are typicallyadministered intravenously. Injectable preparations, for example,sterile injectable aqueous or oleaginous suspensions, may be formulatedaccording to the known art using suitable dispersing or wetting agentsand suspending agents. The sterile injectable preparation may also be asterile injectable solution, suspension or emulsion in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution, and saline (e.g., U.S.P. orisotonic sodium chloride solution). In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid are used inthe preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In certain embodiments, pharmaceutical compositions may be administeredwith or without food. In certain embodiments, pharmaceuticallyacceptable compositions are administered without food. In certainembodiments, pharmaceutically acceptable compositions of this inventionare administered with food.

Specific dosage and treatment regimens for any particular patient willdepend upon a variety of factors, including age, body weight, generalhealth, sex, diet, time of administration, rate of excretion, drugcombination, the judgment of the treating physician, and the severity ofthe particular disease being examined. The amount of a provided compoundor salt thereof in the composition will also depend upon the particularcompound in the composition.

In one embodiment, a composition comprising a compound of the presentinvention is administered intravenously in a trace mass amount and aradioactivity amount to permit safe exposure but sufficient to acquireimages. In some embodiments, the dosage range is from 5-20 mCi persubject. In some embodiments, the dosage range is about, at least about,or at most about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, or 25 mCi or more per subject, or any rangederivable therein.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

EXAMPLES

General.

Common solvents and chemicals were purchased from Aldrich (Milwaukee,Wis.) or VWR International (Randor, Pa.),(E)-1,1,1-trichloro-4-ethoxybut-3-en-2-one from PharmaSys (Cary, N.C.)and t-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate from SantaCruz Biotechnology Inc. (Santa Cruz, Calif.). ¹⁸F-Fluoride was purchasedfrom PETNET Solutions (Palo Alto, Calif.), ¹⁸F Trap & Release Columns (8mg) were purchased from ORTG, Inc. (Oakdale, Tenn.), and HLB plussep-pak cartridge from Waters (Milford, Mass.). Human brain tissuesamples were obtained from Banner Sun Health Research Institute (SunCity, Ariz.), the frozen unfixed samples were sectioned to 5 μm thicksamples and stored at −80° C. NMR spectra were acquired on Bruker AvanceII 400 spectrometer at 298 K. The ¹H spectra were recorded at 400 MHzand the chemical shifts are reported in ppm relative to TMS; the ¹⁹Fspectra were recorded at 376.3 MHz and the chemical shifts are reportedusing TFA as an external reference standardized to −76.55 ppm. A Model521 microwave heater (Resonance Instruments, Skokie, Ill.) was used forradiochemical reactions. The following systems were used to analyze andpurify the products: System A: Analytical LCMS: Waters Acquity UPLCrunning at 0.7 mL/min. Column: Acquity UPLC BEH C18 1.7 μm 2.1×30 mm.Mobile phase A: water with 0.1% formic acid, B: acetonitrile with 0.1%formic acid, linear gradient 5-95% B in 2 min. The system was equippedwith Acquity PDA and Acquity SQ detectors. System B: Preparative HPLC:Waters 2545 pump running at 70 mL/min. Column Phenomenex Gemini-NX 10μ.C18 110A AX 100×30.00 mm. Mobile phase A1: water with 0.1 formic acid,A2: water with 0.1% NH₄OH, B: acetonitrile. Linear gradient A1 or A2 toB in 10 min. System D: Semi-preparative HPLC: Agilent 1290, running at 4mL/min. Column: Phenomenex Luna 5μ. C18 100A, 250×10 mm. Mobile phase A:water with 0.1% formic acid, B: acetonitrile with 0.1% formic acid.System E: Analytical LCMS system consisting of HPLC: Pump: Agilent 1290,running at 0.5 mL/min. Column: Phenomenex Kinetex 2.6μ. C18 100A, 50×2.1mm. Mobile phase A: water with 0.1% formic acid, B: acetonitrile with0.1% formic acid. Linear gradient: 5-95% B in 3 min followed by 95% Bfor 1 min. The LC system is equipped with UV and radioactivity (PMT)detectors and coupled to HRMS Agilent 6220 Accurate-Mass TOF LC/MS massspectrometer (Santa Clara, Calif.). Autoradiography data was collectedon Typhoon FLA 9500 (GE Healthcare Bio-Sciences, Uppsala, Sweden)phosphorimager using FujiFilm Imaging BAS-SR 2025 (Kanagawa, Japan)plates. Human and mice liver microsomes were obtained from BD Gentest(Bedford, Mass.). C57BL/6 mice were purchased from Harlan Laboratories(Livermore, Calif.). Animal care followed protocols approved byGenentech's Institutioned Animal Care and Use Committee, which isaccredited by the Association for Assessment and Accreditation ofLaboratory Animal Care (AAALAC).

Example 1 Synthesis of1,1-dideutero-2-(1-(benzo[4,5]imidazo[1,2-a]pyrimidine-2-yl)piperidin-4-yl)-1-[¹⁸F]fluoroethane([¹⁸F][A]-d2)

¹⁸F-Fluoride trapped on a Trap-and-Release cartridge was eluted using asolution containing TBHCO₃ (150 μL, 0.075 M) in acetonitrile (500 μL)and water (350 μL). The solvent was evaporated using a gentle stream ofnitrogen and microwave heating to 120° C. followed by azeotropic removalof residual water using acetonitrile (4×0.5 mL). The precursor 6 (2 mg)was dissolved in 0.5 mL of acetonitrile and added to a vial containing¹⁸F-fluoride and heated using a microwave heater to 120° C., 50 W for350 s. The reaction mixture was concentrated to approximately 100 μL anddiluted with water (2 mL) for injection to semi-preparative HPLC (SystemD). The product was eluted with 15% B for 10 min followed by 20% B for10-15 min. The fraction containing the product was diluted with water todouble the volume and the product was isolated using HLB plus sep-pakcartridge preconditioned with ethanol (10 mL) and water (10 mL), andeluted with ethanol (3 mL). The ethanol was evaporated to dryness andthe product [¹⁸F][A]-d2 was formulated. The radiochemical purity wasassessed by LCMS (System E).

The identity of [¹⁸F][A]-d2 was confirmed by co-elution with fullycharacterized cold standard [A]-d2 (System E, retention time 1.5 min).The radiochemical purity of [¹⁸F][A]-d2 was 99% (FIG. 5) with a specificactivity of 70,000-110,000 Ci/mmol.

The intermediate compound 6 was prepared as follows.

a. 2-(trichloromethyl)benzo[4,5]imidazol[1,2-a]pyrimidine (1)

2-Amino-benzimidazole (5.0 g, 37.6 mmol) was suspended in toluene (150mL) and triethylamine (5.3 mL, 37.6 mmol) was added.(E)-1,1,1-Trichloro-4-ethoxybut-3-en-2-one was was added at roomtemperature. The resulting mixture was heated to 120° C. for 30 minutes.The solvent was evaporated to provide the crude product as yellow solid10 g (93%). LCMS (System A) m/z found 286.1, calcd for C₁₁H₇C₁₃N₃ (M+H)⁺285.96. ¹H NMR DMSO-d6 δ 9.77 (d, 1H), 8.41 (d, 1H), 7.95 (d, 1H), 7.75(d, 1H), 7.62 (dd, 1H), 7.53 (dd, 1H).

b. 2-hydroxybenzo[4,5]imidazol[1,2-a]pyrimidine (2)

NaOH (49 mL, 1N) was added to compound 1 (10 g, 38 mmol) suspended inacetonitrile (150 mL). The mixture was heated to 90° C. for 2 hours. Themixture was cooled and concentrated to approximately half of theoriginal volume. The mixture was cooled to 0° C. and the pH adjusted to7-8 using 1N HCl. The precipitate was collected and dried to yield crudecompound 2 (6.1 g, 87%). LCMS (System A) m/z found 186.1, calcd forC₁₀H₈N₃O (M+H)⁺ 186.1. ¹H NMR DMSO-d6 δ12.60 (bs, 1H), 8.77 (d, 1H),7.89 (d, 1H), 7.51 (d, 1H), 7.31 (dd, 1H), 7.23 (dd, 1H), 6.10 (d, 1H).

c. 2-bromobenzo[4,5]imidazol[1,2-a]pyrimidine (3)

POBr₃ (30 g, 106 mmol) was added in portions to a suspension of compound2 (6.1 g, 33 mmol) in 1,2-dichloroethane (100 mL) and DMF (1 mL) and themixture was then heated to 100° C. for 1 hour. The reaction mixture wasconcentrated, poured into iced water (100 mL) and the pH was adjusted to8 with concentrated NH₄OH. The precipitate was collected and washed withiced water and dried in vacuo to yield compound 3 as an brown-orangesolid (7.3 g, 89%). LCMS (System A) m/z found 248.1, calcd for C₁₀H₇BrN₃(M+H)⁺ 247.97. ¹H NMR DMSO-d6 δ 9.03 (d, 1H), 8.05 (d, 1H), 7.60 (d,1H), 7.44 (dd, 1H), 7.37 (dd, 1H), 6.42 (d, 1H).

e. 1,1-dideutero-2-(piperidin-4-yl)ethanol (4)

Tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (0.5 g, 2mmol) was dissolved in THF (3 mL) and added drop-wise over 20 min to asuspension of LiAlD₄ (0.25 g, 6 mmol) in THF (3 mL) stirred at roomtemperature. The reaction mixture was stirred for 1 hour then the excessof LiAlD₄ was decomposed using water. The precipitation was removed byfiltration and washed with THF. The organic extracts were concentrated;the oily residue was dissolved in 98% trifluoroacetic acid and stirredat room temperature for 30 minutes. Trifluoroacetic acid was removed atreduced pressure; the oily residue was triturated with toluene and driedin vacuo. The crude compound 4 was obtained as the trifluoroacetate salt(500 mg, 100%) and used without further purification. LCMS (System A)m/z found 132.06, calcd for C₇H₁₄D₂NO (M+H)⁺132.13. ¹H NMR DMSO-d6 δ3.40-3.25 (m, 2H), 2.92-2.82 (m, 2H), 1.92-1.78 (m, 2H), 1.63 (m, 2H),1.25-1.37 (m, 3H), 8.64-8.30 (bd, 2H), 9.12 (bs, 1H).

f. 1,1-dideutero-2-(1-(benzo[4,5]imidazo[1,2-a]pyrimidine-2-yl)piperidin-4-yl)ethanol (5)

A mixture of compound 4 (0.5 g, 2 mmol), diisopropylethylamine (1.4 mL,8 mmol) and 5 (0.5 g, 2 mmol) in DMF (10 mL) was heated to 95° C. for 2hours. The reaction mixture was cooled and poured to iced water (100 mL)and the resulting precipitate was collected and dried in vacuo. Themother liquor containing significant amount of product was evaporated todryness at reduced pressure and the product purified on HPLC (System B,A2 and 5-50% B). Overall 412 mg, (70%) of compound 5 was obtained. LCMS(System A) m/z found 299.3, calcd for C₁₇H₁₉D₂N₄O (M+H)⁺ 299.18. ¹H NMRDMSO-d6 δ 8.93 (d, 1H), 7.93 (d, 1H), 7.50 (dd, 1H), 7.31 (dd, 1H), 7.14(dd, 1H), 6.87 (d, 1H), 4.56 (m, 2H), 4.33 (s, 1H), 3.00 (m, 2H),1.81-1.75 (m, 3H), 1.39 (d, 2H), 1.19-1.09 (m, 2H).

g. 1,1-dideutero-2-(1-(benzo[4,5]imidazo[1,2-a]pyrimidine-2-yl)piperidin-4-yl)-1-bromoethane (6)

A solution of PBr₃ (1M, 0.4 mL) in dichloromethane was added slowly to acooled (0° C.) suspension of compound 5 in dichloromethane. The coolingbath was removed after 10 minutes and the reaction mixture was allowedto warm to room temperature and stirred for 3 hours. The reactionmixture was cooled to 0° C. and an additional portion of PBr₃ solution(0.4 mL) was added. The reaction mixture was stirred overnight at roomtemperature then quenched with few drops of water and concentrated invacuo. The crude product was purified on HPLC (System B, A2 and 20-60%B) to yield compound 6 (20 mg, 17%) as a white solid. LCMS (System A)m/z found 361.15, calcd for C₁₇H₁₈D₂BrN₄ (M+H)⁺ 361.09. ¹H NMR DMSO-d6 δ8.94 (d, 1H), 7.94 (d, 1H), 7.50 (d, 1H), 7.29 (dd, 1H), 7.15 (dd, 1H),6.88 (d, 1H), 4.48 (m, 2H), 3.04 (m, 2H), 1.95 (m, 1H), 1.83 (m, 4H),1.19 (m, 2H).

Example 2 Synthesis of1,1-dideutero-2-(1-(benzo[4,5]imidazo[1,2-a]pyrimidine-2-yl)piperidin-4-yl)-1-fluoroethane([A]-d2)

Diethylaminosulfurtrifluoride (0.17 mL, 1.25 mmol) was added to a cooled(−78° C.) solution of compound 5 (75 mg, 0.25 mmol) in dichloromethane(2 mL). The reaction mixture was allowed to warm to room temperature andstirred for 1 hour. The reaction mixture was then cooled to −78° C. andan additional amount of diethylaminosulfur trifluoride (0.17 mL, 1.25mmol) was added. The reaction mixture was warmed to room temperature andquenched with saturated aqueous solution of NaHCO₃. The mixture wasconcentrated, re-dissolved in DMSO and purified on HPLC (System B, A2and 5-50% B) to yield compound [A]-d2 as white solid (16 mg, 21%). LCMS(System A) m/z found 301.3 calcd for C₁₇H₁₈D₂FN₄ (M+H)⁺ 301.17. ¹H NMRDMSO-d6 δ 1H 8.94 (d, 1H), 7.94 (d, 1H), 7.50 (d, 1H), 7.29 (dd, 1H),7.14 (dd, 1H), 6.88 (d, 1H), 4.57 (m, 2H), 3.01 (m, 2H), 1.84-1.76 (m,3H), 1.58-1.66 (dd, 2H), 1.15-1.24 (m, 2H); ¹⁹F NMR DMSO-d6 δ −219.1.

Example 3 Synthesis of2-(1-(benzo[4,5]imidazo[1,2-a]pyrimidine-2-yl)piperidin-4-yl)-1-fluoroethaneGAD

Diethylaminosulfur trifluoride (0.225 mL, 1.7 mmol) was added to acooled (−78° C.) solution of compound 9 (100 mg, 0.34 mmol) indichloromethane (2 mL). The reaction mixture was allowed to warm to roomtemperature and the quenched with saturated aqueous solution of NaHCO₃.The mixture was concentrated, re-dissolved in DMSO and purified on HPLC(System B, A1 and 5-50% B) to yield compound [A] as a white solid (20mg, 20%). LCMS (System A) m/z found 299.5 calcd for C₁₇H₂₀FN₄ (M+H)⁺299.16. ¹H NMR DMSO-d6 δ 8.94 (d, 1H), 7.94 (d, 1H), 7.50 (d, 1H), 7.28(dd, 1H), 7.14 (dd, 1H), 6.88 (d, 1H), 4.62, 4.46 (dt, 2H), 4.60 (bm,2H), 3.01 (m, 2H), 1.84 (m, 3H), 1.5-1.7 (m, 2H), 1.05-1.3 (m, 2H); ¹⁹FNMR DMSO-d6 δ −217.9.

Example 4 Synthesis of2-(1-(benzo[4,5]imidazo[1,2-a]pyrimidine-2-yl)piperidin-4-yl)-1-[¹⁸F]fluoroethane([¹⁸F][A])

¹⁸F-Fluoride trapped on a Trap-and-Release cartridge was eluted using asolution containing TBHCO₃ (150 μL, 0.075 M) in acetonitrile (500 μL)and water (350 The solvent was evaporated using a gentle stream ofnitrogen and microwave heating to 120° C. followed by azeotropic removalof residual water using acetonitrile (4×0.5 mL). Compound 9 (2 mg) wasdissolved in 0.5 mL of acetonitrile and added to a vial containing¹⁸F-fluoride and heated using a microwave heater to 120° C., 50 W for350 seconds. The reaction mixture was concentrated to approximately 100μL and diluted with water (2 mL) for injection to semi-preparative HPLC(System D). The product was eluted with 15% B for 10 minutes followed by20% B for 10-15 minutes. The fraction containing the product was dilutedwith water to double the volume and the product was isolated using HLBplus sep-pak cartridge preconditioned with ethanol (10 mL) and water (10mL), and eluted with ethanol (3 mL). The ethanol was evaporated todryness and the compound [′⁸F][A] was formulated. The radiochemicalpurity was assessed by LCMS (System E).

The identity of [′⁸F][A] was confirmed by co-elution with fullycharacterized cold standard [A] using (System E, retention time 1.5min). The radiochemical purity of [A] was 99% (FIG. 6) with a specificactivity of 70,000-110,000 Ci/mmol.

The intermediate compound 9 was prepared as follows.

a. 2-(1-(benzo[4,5]imidazo[1,2-a]pyrimidine-2-yl)piperidin-4-yl)ethanol(8)

2-(Piperidin-4-yl)ethanol (0.7 g, 5.4 mmol) and compound 3 (1.0 g 4mmol) were mixed in DMF (12 mL) and the reaction mixture was heated to100° C. for 30 minutes. The suspension was cooled to room temperatureand poured into a 5% aqueous solution of Na₂CO₃ (250 mL). Theprecipitate was collected, washed with iced water and dried to yieldcompound 8 as a brown-orange solid (0.74 g, 61%). LCMS (System A) m/zfound 297.3 calcd for C₁₇H₂₁N₄O (M+H)⁺ 297.16. ¹H NMR DMSO-d6 δ 9.05 (d,1H), 8.04 (d, 1H), 7.53 (d, 1H), 7.40 (t, 1H), 7.29 (dd, 1H), 7.09 (d,1H), 4.59 (m, 2H), 4.37 (bs, 1H), 3.49 (t, 2H), 3.09 (m, 2H), 1.85-1.82(m, 3H), 1.40 (dt, 2H), 1.17-1.13 (m, 2H).

b. 2-(1-(benzo[4,5]imidazo[1,2-a]pyrimidine-2-yl)piperidin-4-yl)ethylp-toluenesulfonate (9)

A solution of p-toluenesulfonyl anhydride (0.7 g, 2.1 mmol) in pyridine(5 mL) was added to a cooled (0° C.) suspension of compound 8 inpyridine (10 mL). The reaction mixture was allowed to warm to roomtemperature and stirred for 2 hours. Another portion of p-toluenesufonylanhydride (0.7 g, 2.1 mmol) was added at room temperature and themixture was stirred for 30 minutes to complete the reaction. Thereaction mixture was poured water (150 mL) and product extracted withdichloromethane (2×50 mL) and the organic extracts were dried overMgSO₄. The crude product was purified on HPLC (System B, A1 and 20-60%B) to yield compound 9 as a p-toluenesulfonate salt (0.29 g, 38%) as ayellowish solid. LCMS (System A) m/z found 451.7, calcd for C₂₄H₂₇N₄O₃S(M+H)⁺ 451.1798; HRMS (System E) m/z found 451.1799. ¹H NMR DMSO-d6 δ9.15 (d, 1H), 8.13 (d, 1H), 7.82 (d, 2H), 7.57 (d, 1H), 7.52-7.40 (m,6H), 7.26 (d, 1H), 7.10 (d, 2H), 4.50 (m, 2H), 4.20 t, 2H), 3.11 (m,2H), 2.44 (s, 3H), 2.28 (s, 3H), 1.70 (m, 3H), 1.6 (m, 2H), 1.06-1.16(m, 2H).

Example 5 Synthesis of2-((1R,5S,6s)-6-(2-fluoroethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-(benzo[4,5]imidazo[1,2-a]pyrimidine-2-yl)([¹⁸F][B])

The synthesis of compound C-1 was based on literature protocol. SeeExample 53 in WO 2004/033451, incorporated herein by reference.

Synthesis of(1S,5R,6s)-6-(2-(tert-butyldimethylsilyloxy)ethyl)-3-azabicyclo[3.1.0]hexane(C-1) and(1R,5S,6s)-6-(2-(tert-butyldimethylsilyloxy)ethyl)-3-azabicyclo[3.1.0]hexane(C-2)

Step 1: benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (C-4)

Pyrrolidine (C-3) (46.9 g, 672 mmol) was dissolved in DCM (700 mL) at 0°C. Cbz-Cl (95.2 g, 560 mmol) was added slowly. The reaction was allowedto warm room temperature and stirred for 14 hours. The solvent wasremoved under reduced pressure and the residue was taken up in ethylacetate. The ethyl acetate solution was washed with 0.5N HCl two times,saturated sodium bicarbonate solution, and brine. It was then dried overMgSO₄ and filtered. The filtrate was removed under reduced pressure andthe residue was purified by silica-gel column chromatography elutingwith 5:1 PE/EA to afford the title compound (46.0 g, 40%) as yellow oil.MS-ESI: [M+H]⁺ 204.3

Step 2: 3-benzyl 6-ethyl(1R,5S,6r)-3-azabicyclo^(3.1.0)hexane-3,6-dicarboxylate (C-5) and3-benzyl 6-ethyl (1R,5S,6s)-3-azabicyclo^(3.1.0)hexane-3,6-dicarboxylate(C-6)

A solution of ethyl diazoacetate (93 mL) in dichloro ethane (720 mL) wasadded slowly (over 5 h) to a mixture of benzyl 3-pyrrolinel-carboxylate(C-4) (36.0 mg) and rhodium(II) acetate (1.27 g) in dichloroethane (360mL). The mixture was heated at 80° C. for 5 hrs. The solvent wasevaporated under reduced pressure. The residue was taken up in 1:1Heptane/EA and filtered through neutral alumina. The filtrate wasevaporated under reduced pressure and the residue was purified bysilica-gel column chromatography eluting with 3:1 Hep/EA (from 3/1 to2/1) to afford the title compounds: C-5 (18.0 g, 35%) and C-6 (10.0 g,19%). MS-ESI: [M+H]⁺ 290.1

Step 3: (1R,5S,6r)-benzyl6-(hydroxymethyl)-3-azabicyclo^(3.1.0)hexane-3-carboxylate (C-7)

At 0° C. to a solution of 3-benzyl 6-ethyl(1R,5S,6r)-3-azabicyclo^(3.1.0)hexane-3,6-dicarboxylate (C-5) (31.8 g,110 mmol) in THF (110 mL) was added a solution of BH₃.THF complex (1M inTHF, 275 mL, 275 mmol). The mixture was stirred at 65° C. for 2 hrs. Thereaction was allowed to cool to room temperature and the solvent wasremoved under reduced pressure. Brine and DCM were added and the layerswere separated. The aqueous layer was acidified to pH 5 with 1M HClsolution and extracted twice with DCM. The combined organic layer wasdried with MgSO₄, filtered, and evaporated under reduced pressure. Theresidue was purified by silica-gel column chromatography eluting with1:1 PE/EA to afford the title compound (24.0 g, 80%) as colorless oil.

MS-ESI: [M+H]⁺ 248.1

Step 4: (1R,5S,6r)-benzyl6-formyl-3-azabicyclo^(3.1.0)hexane-3-carboxylate (C-8)

To a solution of (1R,5S,6r)-benzyl6-(hydroxymethyl)-3-azabicyclo^(3.1.0)hexane-3-carboxylate (C-7) (22.2g, 90 mmol) in dichloromethane (1 L) was added Dess-Martin periodinane(76.32 g, 180 mmol). The mixture was stirred at room temperature for 2hours and quenched with aqueous Na₂S₂O₃ solution. It was then extractedtwice with dichloromethane. The combined extract was washed with brineand saturated NaHCO₃ solution. The organic layer was dried over MgSO4,filtered, and evaporated under reduced pressure. The residue waspurified by silica-gel column chromatography eluting with 5:1 PE/EA toafford the title compound (19.0 g, 80%) as colorless oil.

MS-ESI: [M+H]⁺ 246.1

Step 5: (1S,5R,6s)-benzyl6-vinyl-3-azabicyclo^(3.1.0)hexane-3-carboxylate (C-9)

To a suspension of methyltriphenylphosphonium bromide (34.6 g, 97.2mmol) in THF (80 mL) at 0° C. under N₂ atmosphere was added KHMDS (1.0Min THF, 97.2 mL, 97.2 mmol) dropwise. The mixture was allowed to stir atroom temperature for 1 hour and then cooled to −78° C. A solution of(1R,5S,6r)-benzyl 6-formyl-3-azabicyclo^(3.1.0)hexane-3-carboxylate(C-8) (11.9 g, 48.6 mmol) in dry THF (160 mL) was added slowly. Themixture was warmed to −10° C. and stirred for 1 hour. It was thenquenched with saturated NH₄Cl solution, extracted twice with ethylacetate, dried over MgSO₄, filtered, and concentrated under reducedpressure. The residue was purified by silica-gel column chromatographyeluting with EtOAc/PE (10% to 20) to afford the title compound (8.0 g,67%).

MS-ESI: [M+H]⁺ 244.1

Step 6: (1S,5R,6s)-benzyl6-(2-hydroxyethyl)-3-azabicyclo^(3.1.0)hexane-3-carboxylate (C-10)

To a solution of (1S,5R,6s)-benzyl6-vinyl-3-azabicyclo^(3.1.0)hexane-3-carboxylate (C-9) (11.0 g, 45 mmol)in THF (120 ml) cooled at 0° C. was added a solution of BH₃. THF complex(1M in THF, 67.5 mL, 67.5 mmol) and the mixture stirred for 30 minutes.The reaction was allowed to warm to room temperature and stirred for 1hour. It was then re-cooled to 0° C. and treated carefully with 3N NaOHsolution (37.5 mL), followed by the addition of H₂O₂ (30 percentsolution, 45 mL). The resulting mixture was warmed to 65° C. and stirredfor 2 hours. It was then allowed to cool to room temperature and thesolvent was removed in vacuo. Brine and ethyl acetate were added and thelayers were separated. The aqueous layer was acidified to pH 5 with 1MHCl solution and extracted twice with ethyl acetate. The combinedorganic layer was dried over MgSO₄, filtered, and concentrated underreduced pressure to afford the crude alcohol, which was used in the nextstep without further purification.

MS-ESI: [M+H]⁺ 262.1

Step 7: 2-((1S,5R,6s)-3-azabicyclo^(3.1.0)hexan-6-yl)ethanol (C-1)

To a solution of (1S,5R,6s)-benzyl6-(2-hydroxyethyl)-3-azabicyclo^(3.1.0)hexane-3-carboxylate (C-10) (7.44g, 28.5 mmol) in MeOH (200 mL) was added palladium on carbon (10percent, 2.23 g). The flask was charged with hydrogen gas and stirred atroom temperature for 4 hours. The reaction mixture was then filteredthrough a pad of Celite and the filtrate was concentrated under reducedpressure to afford the crude title compound, which was purified bymass-guided reverse-phase prep-HPLC to afford the title compound as ayellow oil (2.7 g, 75%).

MS-ESI: [M+H]⁺ 128.3

¹H NMR (500 MHz, CDCl₃) δ 4.30 (br s, 2H), 3.70-3.67 (m, 2H), 3.24-3.21(m, 2H), 3.11-3.08 (m, 2H), 1.53-1.49 (m, 2H), 1.41-1.39 (m, 2H),0.92-0.90 (m, 1H).

Step 8:(1R,5S,6s)-6-(2-(tert-butyldimethylsilyloxy)ethyl)-3-azabicyclo[3.1.0]hexane(C-2)

At 0° C. to a solution of2-((1S,5R,6s)-3-azabicyclo[3.1.0]hexan-6-yl)ethanol (C-1) (1.27 g, 10mmol) in dry DMF (30 mL) was added imidazole (1.7 g, 25 mmol) andtert-butyldimethylsilylchloride (1.95 g, 13 mmol). The mixture wasstirred at room temperature for overnight. Ethyl acetate was added andthe solution was washed with brine, 1M HCl solution, dried over MgSO₄),filtered, and concentrated under reduced pressure. The residue waspurified by silica-gel column chromatography eluting with 200:1 ethylacetate/Et₃N to afford the title compound (1.18 g, 49%) as colorlessoil.

MS-ESI: [M+H]⁺ 242.1

¹H NMR (500 MHz, DMSO-d₆) δ 3.57 (t, J=8.0 Hz, 2H), 2.78-2.76 (m, 2H),2.62-2.60 (m, 2H), 1.38-1.35 (m, 2H), 1.11-1.09 (m, 2H), 0.86 (s, 9H),0.61-0.59 (m, 1H), 0.02 (s, 6H).

Synthesis of 2-((1S,5R,6r)-3-azabicyclo[3.1.0]hexan-6-yl)ethanol (D-1)

Step 1: (1R,5S,6s)-benzyl6-(hydroxymethyl)-3-azabicyclo^(3.1.0)hexane-3-carboxylate (D-2)

To a solution of (1R,5S,sr)-3-benzyl 6-ethyl3-aza-bicyclo[3.1.0]hexane-3,6-dicarboxylate (C-6) (10.0 g, 34.6 mmol)in THF (50 mL) at 0° C. was added a solution of BH₃. THF complex (1M inTHF, 70 mL, 70 mmol). The reaction mixture was stirred at 65° C. for 2hrs. The reaction was allowed to cool to room temperature and thesolvent was removed under reduced pressure. To the residue was addedbrine and DCM. The layers of the resulting mixture was separated. Theaqueous layer was acidified to pH 5 with 1M HCl solution and extractedtwice with DCM. The combined organic extract was dried with MgSO₄,filtered, and evaporated under reduced pressure. The residue waspurified by silica-gel column chromatography eluting with 1:1 PE/EA toafford the title compound (6.4 g, 75%) as colorless oil.

MS-ESI: [M+H]⁺ 248.1

Step 2: (1R,5S,6s)-benzyl6-formyl-3-azabicyclo^(3.1.0)hexane-3-carboxylate (D-4)

To a solution of (1R,5S,6s)-benzyl6-(hydroxymethyl)-3-azabicyclo^([3.1.0])hexane-3-carboxylate (D-2) (11.1g, 45 mmol) in dichloromethane (0.5 L) was add Dess-Martin periodinane(38.2 g, 90 mmol). The mixture was stirred at room temperature for 2hours. The reaction was quenched with aqueous Na₂S₂O₃ solution,extracted twice with dichloromethane. The combined extract was washedwith brine and saturated NaHCO₃ solution, dried over MgSO₄, filtered,and evaporated under reduced pressure. The residue was purified bysilica-gel column chromatography eluting with 5:1 PE/EA to afford thetitle compound (9.0 g, 76%) as colorless oil.

MS-ESI: [M+H]⁺ 246.1

Step 3: (1S,5R,6r)-benzyl6-vinyl-3-azabicyclo^([3.1.0])hexane-3-carboxylate (D-5)

To a suspension of methyltriphenylphosphonium bromide (23.1 g, 65 mmol)in THF (60 mL) at 0° C. under N₂ atmosphere was added [KHMDS] (1.0M inTHF, 65 mL, 65 mmol) dropwise. The mixture was allowed to stir at roomtemperature for 1 hour and then cooled to −78° C. A solution of(1R,5S,6s)-benzyl 6-formyl-3-azabicyclo^([3.1.0])hexane-3-carboxylate(D-4) (8.0 g, 32.4 mmol) in anhydrous THF (100 mL) was added slowly andthe mixture was warmed to −10° C. and stirred for 1 hour. The reactionwas quenched with saturated NH₄Cl solution and evaporated under reducedpressure. The residue was extracted twice with ethyl acetate, dried overMgSO₄, filtered, and concentrated under reduced pressure. The residuewas purified by silica-gel column chromatography eluting withEtOAc/hexanes (10% to 20%) to afford the title compound (5.3 g, 66%).

MS-ESI: [M+H]⁺ 244.1

Step 4: (1S,5R,6r)-benzyl6-(2-hydroxyethyl)-3-azabicyclo^([3.1.0])hexane-3-carboxylate (D-6)

To a solution of (1S,5R,6r)-benzyl6-vinyl-3-azabicyclo^([3.1.0])hexane-3-carboxylate (D-5) (5.3 g, 21.7mmol) in THF (60 mL) cooled at 0° C. was added a solution of BH₃.THFcomplex (1M in THF, 32.5 mL, 32.5 mmol). The mixture stirred for 30minutes. The reaction was allowed to warm to room temperature andstirred for 1 hour. It was then re-cooled to 0° C. The mixture wastreated carefully with 3N NaOH solution (18.1 mL), followed by theaddition of H₂O₂ (30 percent solution, 22 mL). The resulting mixture wasstirred at 65° C. for 2 hours. The reaction was allowed to cool to roomtemperature and the solvent was removed under reduced pressure. To theresidue was added brine and athyl acetate. The layers of the resultingmixture were separated. The aqueous layer was acidified with 1M HClsolution to pH 5, extracted twice with ethyl acetate, dried over MgSO₄,filtered, and concentrated under reduced pressure to afford the crudetitle compound, which was used in the next step without furtherpurification.

MS-ESI: [M+H]⁺ 262.1

Step 5: 2-((1S,5R,6r)-3-azabicyclo^([3.1.0])hexan-6-yl)ethanol (D-1)

To a solution of (1S,5R,6r)-benzyl6-(2-hydroxyethyl)-3-azabicyclo^([3.1.0])hexane-3-carboxylate (D-6)(3.72 g, 14.25 mmol) in MeOH (100 mL) was added palladium on carbon (10percent, 1.13 g). The flask was charged with hydrogen gas and stirred atroom temperature for 4 hours. The reaction mixture was then filteredthrough a pad of celite. The filtrate was concentrated under reducedpressure to afford the crude title compound, which was purified bymass-guided reverse-phase prep-HPLC to afford the target compound aswhich solid.

MS-ESI: [M+H]⁺ 128.3

¹H NMR (500 MHz, DMSO-d₆) δ 5.8-5.0 (br s, 2H), 3.47-3.43 (m, 2H),3.38-3.36 (m, 1H), 3.23-3.21 (m, 1H), 3.00-2.98 (m, 1H), 2.82-2.79 (m,1H), 1.55-1.53 (m, 1H), 1.48-1.45 (m, 2H), 1.28-1.24 (m, 1H), 0.88-0.79(m, 1H).

The compounds B-2, B-3, and B-4 were synthesized using proceduressimilar to those above with following yields and analytical data.

Compound B-2 Yellow solid, yield 80-90%. LCMS 295.25 @ 0.82 min >99%.NMR DMSO-d6 400 MHz 9.06 (d, 1H), 8.06 (d, 1H), 7.54 (d, 1H), 7.42 (t,1H), 7.31 (t, 1H), 6.73 (d, 1H), 4.47 (bs, 1H), 3.87 (dd, 2H), 3.66 (m,2H), 3.48 (t, 2H), 1.60 (m, 2H), 1.43 (dq, 2H), 0.63 (m, 1H)

Compound B-3 (cold standard) White solid, yield 26%. LCMS 297.59 @ 0.87min >99%. NMR 300 MHz DMSO-d6 1H 8.95 (d, 1H), 7.95 (d, 1H), 7.50 (d,1H), 7.30 (dt, 1H), 7.17 (dt, 1H), 6.54 (d, 1H), 4.59, 4.43 (dt, 2H),3.7-4.0 (m, 2H), 3.5-3.7 (m, 2H), 1.55-1.8 (m, 4H), 0.64 (m, 1H). 19F−216.62

Compound B-4 (precursor) White solid, yield 75%. LCMS: 357.26 359.25 @1.03 min >99%. NMR 400 MHz DMSO-d4 8.94 (d, 1H), 7.93 (d, 1H), 7.50 (d,1H), 7.29 (dd, 1H), 7.14 (dd, 1H), 6.51 (d, 1H), 3.90-3.80 (m, 2H), 3.59(t, 2H), 3.50-3.70 (m, 2H), 1.83 (dd, 2H), 1.67 (m, 2H), 0.71 (m, 1H)

[18F][B] can be prepared under the similar labeling conditions asdescribed above with a decay corrected yield of 5-10%.

Prophetic Synthesis of [¹⁸F][B]-d2 Oxidation of Amino Alcohol to AminoAcid C-1

H₂IO₆ (85 mg) is suspended in water (1 mL) and acetonitrile (1 mL) andstirred vigorously for 15 min. Amino alcohol (50 mg) is added followedby the addition of pyridinium chlorochromate (5 mg). The reactionmixture is stirred for 2 h at the room temperature and the final productisolated.

Method for Boc Protection of Amino Acid 2-1

To a solution of Compound C-1 in DCM the tert-butyloxycarbonyl anhydride(1.5 eq) and DIEA (3 eq) are added at 0° C. The mixture is allowed towarm to room temperature and stirred until complete conversion.

Synthesis of Methyl Ester 3-1

Freshly prepared solution of diazomethane in ether (Diazald kit) isadded to a solution of Compound 2-2 in dioxane at room temperature. Thereaction is monitored and additional diazomethane solution is added tocomplete the conversion of Compound 2-2 to methylester.

Synthesis of Dideutero Amino Alcohol 4-1

The methylester (Compound 3-1) is reduced with LiAlD₄ to deuteratedalcohol and deprotected with TFA to provide Compound 4-1 as describedabove.

The remaining steps track those shown for [¹⁸F][A]-d2.

Synthesis of Additional Compounds

Using procedures similar to those described herein, the followingcompounds of formula (I) can also be prepared:

Example 6 Biological Evaluation Autoradiography

The tracer [¹⁸F][A] or [¹⁸F][A]-d2 was dissolved in PBS containing 5%DMSO and 5% ethanol at final concentration 40 μCi/mL. Then 0.5 ml ofstock solution was transferred to a microscope slide with 5 μm thickfreshly dried section of a tissue and incubated for 90 min at roomtemperature. The slides were washed by dipping into following solutions:PBS for 1 min, 70% ethanol 2 min, 30% ethanol 2 min and PBS 1 min. Thesamples were dried at room temperature for 30 min and exposed tophosphorimager plate for 20 h. The exposed plates were scanned at 25 μmresolution.

MicroPET Imaging

The PET imaging was performed on Inveon PET/CT scanner (Siemens MedicalSolutions USA Inc.). Animals anesthetized with sevoflurane were placedhead-first, prone position on the scanner bed and dynamic 45 min scanswere initiated. Approximately 3.7 MBq of ¹⁸F-radiolabeled tracer inisotonic solution (100-130 μL) was administered as 60 second intravenousinfusion via the tail vein. Body temperature was measured by a rectalprobe and maintained with warm air flow at 37° C. Full-body iterativeimage reconstructions were obtained using maximum a posteriori algorithm(MAP, hyperparameter β 0.05) and corrected for signal attenuation usingthe tissue density obtained from CT. Projections were created with PMOD3.305 (PMOD Technologies, Ltd., Zurich, Switzerland) and used to obtainquantitative activity levels in each organ of interest usingregion-of-interest analysis.

Microsomal Stability Assays

The tracer [¹⁸F][A]-d2 or [¹⁸F][A] was dissolved in potassium phosphate(Kpi) buffer (100 mM) at concentration 500-600 μCi/mL. Thenon-radioactive 7 and 10 were dissolved in Kpi buffer at 10 μMconcentration. The reaction vessel was charged with human or mouse livermicrosome suspension (12.5 μL, 20 mg/mL) followed by Kpi buffer (388 μL,10 mM), NADPH (50 μL, 10 mM) and incubated at 37° C. for 5-10 min. Asolution of the radioactive [¹⁸F][A]-d2 or [¹⁸F][A] (50 μL, 250-300 μCi)or non-radioactive 7 or 8 (50 μL, 10 μM) were added to the reactionvessel and the mixture was incubated at 37° C. Aliquots (50 μL) of thereaction mixture were taken at 5, 15 and 45 minutes post addition of thetested compound, mixed with ice-cold acetonitrile (100 μL) andcentrifuged. The supernatant was analyzed by LCMS (System E).

Statistical Analysis

The statistical analysis was performed and the plots were constructedwith R software version 2.10.1 (R Foundation for Statistical Computing,Vienna, Austria). Statistical significance was determined usingStudent's t-test and p of less than 0.05 was considered significant. Alldata are presented as mean±standard deviation.

Results and Discussions

Both [¹⁸F][A] and [¹⁸F][A]-d2 were prepared in a single step usingin-situ generated [¹⁸F]TBAF. After HPLC purification, [¹⁸F][A]-d2 wasobtained in 7% decay corrected radiochemical yield within 90 minutes(n=4); [¹⁸F][A] was prepared in 12% yield within 96 min (n=9). Theradiochemical purity of both tracers was greater than 99% and specificactivity in the range of 70-110 Ci/μmol.

Autoradiographic evaluation of [¹⁸F][A] and [¹⁸F][A]-d2 was performedusing brain tissues collected postmortem from human donors. Bothcompounds, [¹⁸F][A] and [¹⁸F][A]-d2, showed identical tau specificbinding patterns (FIG. 1). The positive staining was found in greymatter of tissues containing high level of NFTs and high Aβ-amyloidcharacterized as Braak score 5. The negative control tissues containinghigh or moderate Aβ-amyloid burden but no NFTs with Braak score 3 or 2were not positively stained with either [¹⁸F][A] or [¹⁸F][A]-d2. The NFTand A3-amyloid burden was measured by standard immunohistochemicalmethods.

The metabolic stability and [¹⁸F]F⁻ formation was assessed in vitrousing human and mice liver microsomes (Tipre, D. N, et al., J. Nucl.Med. 2006 47 (2), 345-53). Slower metabolism of [A] in human than inmouse liver microsome assay was reported, in both species, themetabolism of [A] was NADPH dependent indicating possible involvement ofcytochrome P450 enzymes (Zhang, W., et al., J. Alzheimer's Disease:JAD2012 31 (3), 601-12). A comparison of non-radiolabled [A] and [A]-d2 inliver microsome assay revealed a higher stability of [A]-d2 compared to[A] in both human and mouse liver microsomes. The metabolism of [A] and[A]-d2 in mouse liver microsomes was very rapid, the fraction ofunmetabolized [A] decreased to 2% at 5 min but the amount of [A]-d2 was11% (FIG. 3B) In human liver microsomes, the amount of remaining [A] was15% at 40 min but [A]-d2 amount was still 56% (FIG. 3A). The metabolismof both [A] and [A]-d2 was NADPH dependent suggesting the involvement ofcytochrome P450 enzymes.

The radiolabeled tracers [¹⁸F][A] and [¹⁸F][A]-d2 (n=3) were alsoincubated with human or mouse liver microsome suspensions with orwithout NADPH at 37° C. and the mixture was analyzed for a presence ofradioactive metabolites at 5, 15 and 45 min (FIG. 2). In the presence ofmouse liver microsomes, both the [¹⁸F][A] and [¹⁸F][A]-d2 metabolizedrapidly to ¹⁸F-fluoride (retention time (rt)=0.38 min), and tworadioactive metabolites M2 and M1 (rt=1.2 and 1.4 min). The conversionof [¹⁸F][A] and [¹⁸F][A]-d2 to M2 and M1 was very fast and the amount ofparent compound (rt=1.5 min) was only 1.6±0.9% and 2.0±0.3 respectively(FIG. 2D) at 5 minutes. At 45 minutes, the amount of [¹⁸F]F⁻ formed from[¹⁸F][A] (50.1±12.9%) was significantly (p=0.035) larger compared to theamount of [¹⁸F]F⁻ formed from [¹⁸F][A]-d2 (13.8±2.4%) (FIG. 2B). In thepresence of human liver microsomes, the conversion of both tracers to[¹⁸F]F⁻, M1 and M2 was slower than in mouse liver microsomes.Nevertheless, [¹⁸F][A] was still metabolized more rapidly thandideuterated [¹⁸F][A]-d2. After 45 min incubation with human livermicrosomes, the fraction attributed to parent compound ([¹⁸F][A]) was35.7±0.9% and the fraction of radioactivity attributed to [¹⁸F][A]-d2was 91.7±0.21% (FIG. 2C). The amount of [¹⁸F]F⁻ was 36.7±2.7% in case of[¹⁸F][A] but no [¹⁸F]F⁻ was detected as a product of [¹⁸F][A]-d2metabolism in human liver microsomes at 45 minutes (FIG. 2A).

Dynamic PET imaging in mice (n=6) was used to assess in vivo propertiesof [¹⁸F][A] and [¹⁸F][A]-d2. The uptake of both tracers wasindistinguishable in liver and kidneys (FIG. 4E, 4D). The peak uptakesin brain (8.3±2.0 and 7.4±2.2% ID/g) were not significantly differentbetween the tracers (p=0.444) (FIG. 4C) as well as the blood signalobtained from whole heart (FIG. 4B). However, the mice injected with[¹⁸F][A]-d2 showed significantly (p=1.19×10⁻⁴) reduced bone uptake(14.3±1.7% ID/g) at 30-45 min post tracer injection compared to the boneuptake of mice injected with [A] (31.2±4.8% ID/g) as a consequence ofslower enzymatic defluorination (FIG. 4A). The maximum intensityprojections (FIG. 4F) illustrate the improvements in image quality. ThePET imaging data is in excellent agreement with results of thecomparison of [¹⁸F][A] and [¹⁸F][A]-d2 in vitro using mouse livermicrosomes. In the in vitro experiment the substitution of geminalhydrogens in [¹⁸F][A] with deuterium caused 73% reduction in [¹⁸F]F⁻formation and the reduction in bone uptake observed by in vivo PET isalso close to 54%.

The in vitro and in vivo comparison of [¹⁸F][A]-d2 and [¹⁸F][A] suggeststhat [¹⁸F][A]-d2 is more metabolically stable leading to significantlyless [¹⁸F]F⁻ formation than [¹⁸F][A]. The data also demonstrate that the[A]-d2 metabolism and formation of [¹⁸F]F⁻ in human is expected to bemuch lower than in mouse, hence the [¹⁸F][A]-d2 could providetau-specific images with significantly lower background than [¹⁸F][A] inclinical setting.

Further Studies

The radiolabeled tracers [¹⁸F][A] and [′⁸F][A]-d2 (n=3) were incubatedwith human, rhesus or mouse liver microsome suspension with or withoutNADPH at 37° C. and the mixture was analyzed for a presence ofradioactive metabolites at 5, 15 and 45 min. In the presence of mouseand rhesus liver microsomes, both the [¹⁸F][A] and [¹⁸F][A]-d2metabolized rapidly to ¹⁸F-fluoride (retention time (rt)=0.38 min), andtwo radioactive metabolites M2 and M1 (rt=1.2 and 1.4 min). Theconversion of [¹⁸F][A] and [¹⁸F][A]-d2 to M2 and M1 was very fast andthe amount of parent compound (rt=1.5 min) was only 1.6±0.9% and 2.0±0.3respectively at 5 min (FIG. 7E) in presence of mouse liver microsomes.Both compounds were slightly more stable in rhesus liver microsomes(FIG. 7F). At 45 min, the amount of [¹⁸F]F⁻ formed from [¹⁸F][A](50.1±12.9%) was significantly (p=0.035) larger than the amount of[¹⁸F]F⁻ formed from [¹⁸F][A]-d2 (13.8±2.4%) in mouse liver microsomes(FIG. 7B) and a similar effect was observed in rhesus liver microsomes([¹⁸F][A]-d2: 15.4±1.3% vs. [¹⁸F][A]: 46.1±1.0%) (FIG. 7C). In thepresence of human liver microsomes, the conversion of both tracers to[¹⁸F]F⁻, M1 and M2 was slower than in mouse or rhesus liver microsomes.Nevertheless, [¹⁸F][A] was still metabolized more rapidly thandideuterated [¹⁸F][A]-d2. After 45 min incubation with human livermicrosomes, the fraction attributed to parent compound ([¹⁸F][A]) was35.7±0.9% and the fraction of radioactivity attributed to [¹⁸F][A]-d2was significantly higher 67.1±6.3% (p=0.012) (FIG. 7D). The amount of[¹⁸F]F⁻ was 36.7±2.7% in case of [¹⁸F][A] but no [¹⁸F]F⁻ was detected(p=0.002) as a product of [¹⁸F][A]-d2 metabolism in human livermicrosomes at 45 min (FIG. 7A).

The microsomal stability assessment as a predictor of in-vivo stabilityof [¹⁸F][A] and [¹⁸F][A]-d2 suggests significantly higher metabolicstability of [¹⁸F][A]-d2 compared to [¹⁸F][A] and significantly slowerrate of ¹⁸F-fluoride formation in rhesus and mice. Unexpectedly,¹⁸F-fluoride was not detected as a metabolite of [¹⁸F][A]-d2 using humanliver microsomes at all, suggesting much greater stability of[¹⁸F][A]-d2 in human than in rhesus or mice.

These PET images acquired in mice and rhesus using [¹⁸F][A] and[¹⁸F][A]-d2 further confirmed the in-vitro prediction of lower¹⁸F-fluoride formation seen as an uptake of radioactivity in mineralbone in case of [¹⁸F][A]-d2 compared to [¹⁸F][A].

Administration of [¹⁸F][A]-d2 in Primates

[¹⁸F][A]-d2, [¹⁸F][A] or ¹⁸F T807 (see Chien et al., J. Alzheimers Dis,38:171-84 (2014)) (370 MBq (10 mCi)) was intravenous bolus injected intoan anesthetized rhesus, and dynamic PET data acquired over 240 minutes.Standard Uptake Values ([Radioactivity]/(injected dose/body weight))were measured in the indicated structures from the reconstructed PETdata (as shown in FIGS. 8A, 8B). Data was collected from the same animalbut on different days for each probe. [¹⁸F][A]-d2 exhibited increasedstability reflected by a reduction of skull uptake of free fluoride.

Human Administration of [¹⁸F][A]-d2

A total of 5 subjects, 3 Alzheimer's disease (AD) patients and 2 healthyvolunteers (HV) was used in this study. This study protocol requiredeach subject to complete the following components: screening evaluation,MM, [¹⁸F]florbetapir (AD subjects only) and [¹⁸F][A]-d2. The screeningprocedures included neuropsychological assessment, vital signs, ECG,physical exam, MRI, and [¹⁸F]florbetapir PET imaging to confirm presenceof amyloid deposition in patients clinically diagnosed with probable AD.In addition, each subject completed clinical assessments and clinicalsafety labs to ensure the subject was medically stable to complete thestudy protocol. The screening procedures occurred within 30 days priorto [¹⁸F][A]-d2 imaging. Eligible subjects participated in a single[¹⁸F][A]-d2 imaging session. The distribution of tau binding wasassessed in each of the subject groups (AD and HV) to evaluate forbinding to tau. For each AD subject, the distribution of Aβ and tau wascompared. Tau binding in brain was assessed with PET using [¹⁸F][A]-d2.Radioligand binding was compared in brains of HV subjects who shouldhave minimal to negligible concentrations of tau compared to patientswith AD, who are expected to have moderate to high densities of tau.

All subjects received a single injection of [¹⁸F][A]-d2. Subjectsreceived a bolus intravenous injection of no more than 370 MBq (˜10mCi). Data pertaining to 3 subjects are presented below.

Imaging Procedure

Images were acquired using a HR+PET camera in three-dimensional mode andwere reconstructed using an iterative algorithm including scatter andmeasured attenuation correction (⁶⁸Ge source). Dynamic images wereacquired upon injection (˜370 MBq). The scanning protocol consisted of 2scanning segments in the two healthy control (HC) subjects, Subjects 1 &2 (0-120 min and ˜150-180 min) and of 3 segments in the suspected ADpatient, Subject 3 (0-60 min, 93-123 min and 147-177 min).

[¹⁸F][A]-d2 Image Analysis and Preliminary Results

The MR volumetric image, a summed image of the first 15 min after traceradministration of [¹⁸F][A]-d2 were coregistered using StatisticalParametic Mapping SPM8 (software provided by members and collaboratorsof the Welcome Trust Centre for Neuroimaging). Alignment of theadditional PET segments to the first PET segment was performed usingin-house developed analysis software written in Matlab® (version 8Release 2014a). Then, using the MRI scan for anatomical delineation,irregular regions of interest (ROI) were drawn for each subject in thefrontal, parietal, occipital, and temporal lobes, cerebellum gray, andwhite-matter (centrum semi-ovale) using MIM® software.

[¹⁸F][A]-d2 tissue time activity curves (TAC) were expressed in SUV(Standardized Uptake Value) using each subject's weight and thecorresponding tracer injected dose: TAC(SUV)=TAC(Bq/cm³)×1000cm³/kg×Subject's weight(kg)/Injected dose(Bq). TAC creation and allsubsequent analyses were performed using in-house developed analysissoftware written in Matlab®.

The ratio to cerebellum gray or standardized uptake value ratio (SUVR)was calculated. FIG. 9 shows the temporal lobe SUVR vs. mean frame timein the 3 subjects. A clear separation of the curves is observed as earlyas 30 min post injection. The SUVR curves in the two healthy controlsremained relatively constant soon after injection. The SUVR in the ADsubject reached a plateau in the 90-120 min interval.

The average values in the 40-60 min and 90-120 min intervals followingtracer injection are shown in Tables 1 and 2, respectively. SUVR valuesare larger in the AD subject, consistent with increased tau burden inthe brain.

TABLE 1 SUVR values in the 40-60 min interval following [¹⁸F][A]-d2administration. Cerebellum gray as reference region Frontal ParietalTemporal Occipital White Subject lobe lobe lobe lobe matter 1 (HC) 1.081.09 1.14 1.15 0.85 2 (HC) 1.12 1.13 1.18 1.19 0.80 3 (AD) 1.16 1.351.82 1.60 0.88

TABLE 2 SUVR values in the 90-120 min interval following [¹⁸F][A]-d2administration. Cerebellum gray as reference region Frontal ParietalTemporal Occipital White Subject lobe lobe lobe lobe matter 1 (HC) 1.071.07 1.13 1.19 0.76 2 (HC) 1.17 1.07 1.18 1.21 0.66 3 (AD) 1.25 1.522.25 1.87 0.81

The images of FIG. 10 acquired in Subjects 1-3 using [¹⁸F][A]-d2 show noradioactivity uptake in bone tissue as predicted by the in-vitromicrosomal stability assay. Lack of uptake in the skull suggestsnegligible tracer defluorination.

While a number of embodiments have been described, these examples may bealtered to provide other embodiments that utilize the compounds andmethods described herein. Therefore, the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

We claim:
 1. A deuterated compound of formula (I) or formula (V):

or a salt thereof, wherein: R¹ is phenyl, naphthyl, 6-memberedheteroaryl, 9- or 10-membered bicyclic heterocyclyl, 12-13 memberedtricyclic carbocyclyl, or 12-13 membered tricyclic heterocyclyl, whereinR¹ is optionally substituted with one or more groups R^(a), wherein R¹is attached to the remainder of the compound of formula (I) at anysynthetically feasible position; A is absent, C₁₋₄alkylene,C₃₋₆cycloalkylene, C₂₋₄alkenylene, or C₂₋₄alkynylene; R² is 6-, 9-, or10-membered carbocyclyl or a 5-, 6-, 9-, or 10-membered heterocyclyl,which carbocyclyl and heterocyclyl is optionally substituted with one ormore groups R^(b), wherein R² is attached to the remainder of thecompound of formula (I) at any synthetically feasible position; eachX₁₀-X₁₇ is independently CH or N; X₁₈ is CH, N, O, or S; and X₁₉ is CH,C, or N; each ---- is independently absent or forms a double bond,provided only one ---- forms a double bond; each R^(a) is independentlyselected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,—(O—CH₂—CH₂)_(m)—R^(c), carbocyclyl, heterocyclyl, halo, —NO₂,—N(R^(v))₂, —CN, —C(O)—N(R^(v))₂, —S(O)—N(R^(v))₂, —S(O)₂—N(R^(v))₂,—O—C(O)—R^(v), —O—C(O)—O—R^(v), —C(O)—R^(v), —C(O)—O—R^(v), —S(O)—R^(v),—S(O)₂—R^(v), —O—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—OR^(v),—N(R^(v))—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v),—N(R^(v))—S(O)₂—R^(v), —N(R^(v))—S(O)—N(R^(v))₂, and—N(R^(v))—S(O)₂—N(R^(v))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(c), carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom oxo, halo, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(v))₂, —S(O)—N(R^(v))₂,—S(O)₂—N(R^(v))₂, —S—R^(v), —O—C(O)—R^(v), —C(O)—R^(v)—S(O)₂—R^(v),—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v),—N(R^(v))—S(O)₂—R^(v), C₂-C₆ alkenyl, R^(ay), and C₁₋₆alkyl that isoptionally substituted with one or more groups independently selectedfrom oxo and halo; each R^(b) is independently selected from oxo,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(d),carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^(w))₂, —CN, —C(O)—N(R^(w))₂,—S(O)—N(R^(w))₂, —S(O)₂—N(R^(w))₂, —O—R^(w), —S—R^(w), —O—C(O)—R^(w),—O—C(O)—O—R^(w), —C(O)—R^(w), —C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w),—O—C(O)—N(R^(w))₂, —N(R^(w))—C(O)—OR^(w), —N(R^(w))—C(O)—N(R^(w))₂,—N(R^(w))—C(O)—R^(w), —N(R^(w))—S(O)—R^(w), —N(R^(w))—S(O)₂—R^(w),—N(R^(w))—S(O)—N(R^(w))₂, and —N(R^(w))—S(O)₂—N(R^(w))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(d),carbocyclyl, and heterocyclyl is optionally substituted with one or moregroups independently selected from oxo, halo, —NO₂, —N(R^(w))₂, —CN,—C(O)—N(R^(w))₂, —S(O)—N(R^(w))₂, —S(O)₂—N(R^(w))₂, —O—R^(w), —S—R^(w),—O—C(O)—R^(w), —C(O)—R^(w), —C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w),—C(O)—N(R^(w))₂, —N(R^(w))—C(O)—R^(w), —N(R^(w))—S(O)—R^(w),—N(R^(w))—S(O)₂—R^(w), C₂-C₆ alkenyl, R^(y), and C₁₋₆alkyl that isoptionally substituted with one or more groups independently selectedfrom oxo and halo; each R^(c) is independently selected from hydrogen,halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, andheterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,carbocyclyl and heterocyclyl is optionally substituted with one or moregroups independently selected from halo, hydroxy, and C₁₋₆alkoxy; eachR^(d) is independently selected from hydrogen, halo, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein eachC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom halo, hydroxy, and C₁₋₆alkoxy; each R^(v) is independently selectedfrom hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, andheterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,carbocyclyl, and heterocyclyl is optionally substituted with one or moregroups independently selected from oxo, cyano, nitro, halo, —N(R^(ax))₂,—OR^(ax), C₂-C₆ alkenyl, R^(ay), and C₁-C₆ alkyl that is optionallysubstituted with one or more groups independently selected from oxo andhalo; or two R^(v) are taken together with the nitrogen to which theyare attached to form a heterocyclyl that is optionally substituted withone or more groups independently selected from oxo, halo and C₁₋₃alkylthat is optionally substituted with one or more groups independentlyselected from oxo and halo; each R^(w) is independently selected fromhydrogen, C₁₋₆alkyl, C₂ alkenyl, C₂₋₆alkynyl, carbocyclyl, andheterocyclyl, wherein each C₁₋₆alkyl, C₂ alkenyl, C₂₋₆alkynyl,carbocyclyl, and heterocyclyl is optionally substituted with one or moregroups independently selected from oxo, cyano, nitro, halo, —N(R^(x))₂,—OR^(x), C₂-C₆ alkenyl, R^(y), and C₁-C₆ alkyl that is optionallysubstituted with one or more groups independently selected from oxo andhalo; or two R^(w) are taken together with the nitrogen to which theyare attached to form a heterocyclyl that is optionally substituted withone or more groups independently selected from oxo, halo and C₁₋₃alkylthat is optionally substituted with one or more groups independentlyselected from oxo and halo; each R^(x) is independently selected fromhydrogen and C₁₋₆alkyl; each R^(ax) is independently selected fromhydrogen and C₁₋₆alkyl; each R^(y) is aryl that is optionallysubstituted with one or more groups independently selected from halo,hydroxyl, cyano, nitro, amino, —O—S(O)₂—R^(z), —OSi(R^(z))₃, and—O-(heterocyclyl); each R^(ay) is aryl that is optionally substitutedwith one or more groups independently selected from halo, hydroxyl,cyano, nitro, amino, —O—S(O)₂—R^(az), —OSi(R^(az))₃, and—O-(heterocyclyl); each R^(z) is independently selected from C₁₋₆alkyland aryl; each R^(az) is independently selected from C₁₋₆alkyl and aryl;each m is 1, 2, 3, 4, or 5; and each n is 1, 2, 3, 4, or 5; wherein thecompound of formula (I) and formula (V) optionally comprises one or moreimaging isotopes; wherein one or more carbon atoms of the compound offormula (I) and formula (V) is deuterated; and wherein the compound offormula (V) is substituted with one or more groups R^(a).
 2. Thedeuterated compound of claim 1 which is a compound of formula (I) or asalt thereof.
 3. The deuterated compound of claim 2 wherein R¹ is a 9-or 10-membered bicyclic heteroaryl ring.
 4. The deuterated compound ofclaim 2 wherein R¹ is:

wherein: X₈ is CH or N; and X₉ is CH₂, NH, O, or S; wherein R¹ isoptionally substituted with one or more groups R^(a).
 5. The deuteratedcompound of claim 2 wherein R¹ is:

wherein R¹ is optionally substituted with one or more groups R^(a). 6.The deuterated compound of claim 2 wherein R¹ is:

wherein: each X₁₀-X₁₇ is independently CH or N; and X₁₈ is CH₂, NH, O,or S; wherein R¹ is optionally substituted with one or more groupsR^(a).
 7. The deuterated compound of claim 2 wherein R¹ is:

and is optionally substituted with one or more groups R^(a).
 8. Thedeuterated compound of claim 2 wherein A is absent or ethynyl.
 9. Thedeuterated compound of claim 2 wherein R² is a 6-membered carbocyclylthat is optionally substituted with one or more groups R^(b).
 10. Thedeuterated compound of claim 1 which is a compound of formula (V), or asalt thereof.
 11. The deuterated compound of claim 10 which is acompound of formula (Va):

or a salt thereof, wherein the compound of formula (Va) is substitutedwith one or more groups R^(a).
 12. The deuterated compound of claim 1wherein the compound comprises an imaging isotope.
 13. The deuteratedcompound of claim 1 wherein the imaging isotope is ¹⁸F.
 14. Thedeuterated compound of claim 1 having the formula (Ia): or a saltthereof, wherein:

R² is 6-membered carbocyclyl or a 5- or 6-membered heterocyclyl, whichcarbocyclyl and heterocyclyl is optionally substituted with one or moregroups R^(b); each R^(b) is independently selected from C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(d), carbocyclyl,heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(w))₂, —CN, —C(O)—N(R^(w))₂,—O—C(O)—R^(w), —C(O)—R^(w), and —C(O)—O—R^(w), wherein any C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(d), carbocyclyl, andheterocyclyl is optionally substituted with one or more groupsindependently selected from oxo, halo, —O—R^(w), —O—C(O)—R^(w),—C(O)—R^(w), —C(O)—O—R^(w), —C(O)—N(R^(w))₂, and —N(R^(w))—C(O)—R^(w).15. The deuterated compound of claim 1 having the formula (Ib):

or a salt thereof, wherein: R^(b) is deuterated and is selected fromC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(d),carbocyclyl, heterocyclyl, —N(R^(w))₂, —C(O)—N(R^(w))₂, —O—C(O)—R^(w),—C(O)—R^(w), and —C(O)—O—R^(w), wherein any C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(d), carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom oxo, halo, —O—R^(w), —O—C(O)—R^(w), —C(O)—R^(w), —C(O)—O—R^(w),—C(O)—N(R^(w))₂, and —N(R^(w))—C(O)—R^(w); and R^(b) comprises one ormore imaging isotopes.
 16. The deuterated compound of claim 1 having theformula (Ic):

or a salt thereof, wherein: R^(b) is deuterated and is selected fromC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(d),carbocyclyl, heterocyclyl, —N(R^(w))₂, —C(O)—N(R^(w))₂, —O—C(O)—R^(w),—C(O)—R^(w), and —C(O)—O—R^(w), wherein any C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(d), carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom oxo, halo, —O—R^(w), —O—C(O)—R^(w), —C(O)—R^(w), —C(O)—O—R^(w),—C(O)—N(R^(w))₂, and —N(R^(w))—C(O)—R^(w); and R^(b) comprises one ormore imaging isotopes.
 17. The deuterated compound of claim 1 having theformula (Id):

or a salt thereof, wherein: R^(b) is deuterated and is selected fromC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(d),carbocyclyl, heterocyclyl, —N(R^(w))₂, —C(O)—N(R^(w))₂, —O—C(O)—R^(w),—C(O)—R^(w), and —C(O)—O—R^(w), wherein any C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, —(O—CH₂—CH₂)_(m)—R^(d), carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom oxo, halo, —O—R^(w), —O—C(O)—R^(w), —C(O)—R^(w), —C(O)—O—R^(w),—C(O)—N(R^(w))₂, and —N(R^(w))—C(O)—R^(w); and R^(b) comprises one ormore imaging isotopes.
 18. The deuterated compound of claim 1 whereineach R^(a) is independently selected from C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, and —O—R^(v); and each R^(v) is independently selected fromhydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, andheterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,carbocyclyl, and heterocyclyl is optionally substituted with one or moregroups independently selected —OR^(ax).
 19. The deuterated compound ofclaim 1 wherein each R^(b) is independently selected from C₂₋₆alkenyl,C₂₋₆alkynyl, and —O—R^(w), wherein any C₁₋₆alkyl, C₂₋₆alkenyl, andC₂₋₆alkynyl is optionally substituted with one or more groupsindependently selected from —O—R^(w); and each R^(w) is independentlyselected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substitutedwith one or more groups independently selected from —OR^(x); wherein atleast one R^(b) is deuterated and comprises one or more imagingisotopes.
 20. The deuterated compound of claim 1 that comprises a carbonatom that is both deuterated and covalently bonded to an imagingisotope.
 21. The deuterated compound of claim 1 wherein R^(b) is—CH₂-*CD₂-¹⁸F, wherein the carbon marked * is deuterated.
 22. Thedeuterated compound of claim 1 wherein R^(b) is —CH₂-*CD₂-¹⁸F, whereinthe carbon marked * has a deuterium isotopic enrichment factor of atleast
 3500. 23. The deuterated compound of claim 1 wherein R^(b) is—CH₂—CH₂—O-*CD₂-*CD₂-¹⁸F, wherein each carbon marked * is deuterated.24. The deuterated compound of claim 1 wherein R^(b) isCH₂—CH₂—O-*CD₂-*CD₂-¹⁸F, wherein each carbon marked * has a deuteriumisotopic enrichment factor of at least
 3500. 25. The deuterated compoundof claim 1 having the formula (Ie):

wherein the carbon marked * has a deuterium isotopic enrichment factorof at least
 3500. 26. The deuterated compound of claim 1 which is thecompound:

or a salt thereof.
 27. The deuterated compound of claim 1 which is acompound selected from:

and salts thereof.
 28. A pharmaceutical composition comprising adeuterated compound as described in claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable diluent orcarrier.
 29. A method for detecting neurofibrillary tangles and/orsenile plaques in an animal comprising administering a deuteratedcompound comprising an imaging isotope as described in claim 1, or apharmaceutically acceptable salt thereof, to the animal, and measuringthe radioactive signal of the compound.
 30. A method of detecting aneurological disorder associated with amyloid plaque and/or tau proteinaggregation in an animal comprising administering a deuterated compoundcomprising an imaging isotope as described in claim 1, or apharmaceutically acceptable salt thereof, to the animal, and measuringthe radioactive signal of the compound, which is associated with amyloiddeposits and/or tau protein aggregates.
 31. A method of detectingAlzheimer's disease associated with amyloid plaque and/or tau proteinaggregation in an animal comprising administering a deuterated compoundcomprising an imaging isotope as described in claim 1, or apharmaceutically acceptable salt thereof, to the animal, and measuringthe radioactive signal of the compound associated with amyloid depositsand/or tau protein aggregates.
 32. A method of detecting progressivesupranuclear palsy associated with amyloid plaque and/or tau proteinaggregation in an animal, comprising administering a deuterated compoundcomprising an imaging isotope as described in claim 1, or apharmaceutically acceptable salt thereof, to the animal, and measuringthe radioactive signal of the compound associated with amyloid depositsand/or tau protein aggregates.